Delivery systems for control of bleeding in transurethral prostatectomy

ABSTRACT

The present disclosure relates to a gastrointestinal delivery device of a chitosan dressing, where the delivery device is capable of stop bleeding, in particular in connection with TURP procedures. The delivery device may be used in all gastrointestinal bleeding applications and can be used with a biocompatible, foldable, thin profile, chitosan dressing. Various aspects of the device and its uses are provided herein.

GOVERNMENT LICENSE RIGHTS

This invention was made with Government support under R42DK078400awarded by National Institute of Diabetes and Digestive and KidneyDisease. The Government has certain right in the invention.

BACKGROUND Technical Field

This disclosure relates to the field of delivery systems for control ofbleeding in transurethral prostatectomy by delivery and application ofdressings and uses thereof.

Description of the Related Art

Current bleeding control in and after transurethral resection of theprostate (TURP) relies on cautery for small vessel arterial bleeding andapplication of balloon pressure to address venous oozing. The bladderneck and prostrate are both highly vascularized tissue that oftencontinue to bleed following injury and through wound healing. Theinitial injury site may continue to bleed for days unless standardhemostasis is applied and the bleeding may also recur around week one orweek two after TURP procedure when the scab of prostatic cavity shedsoff. Current standard initial hemostasis for treatment of bleedingfollowing TURP is to apply manual traction with a balloon catheterfollowed by continuous bladder irrigation with saline. Typically,balloon pressure can be applied for up to 24 hours in the case ofprotracted bleeding. If the bleeding is uncontrollable after the periodof conservational management, the patient may have to return to surgicalunit promptly to stop the hemorrhaging with either open or endoscopicprocedures.

Although there have been advances in bleeding control using advanceddressings for applications outside of TURP bleeding control, none ofthese advances have yet translated to the unique conditions of thebladder and the prostrate where delivery, adhesion, continuous oozingbleeding and urine considerations are highly challenging. Rapid bleedingcontrol in TURP, in open prostatectomy and in bladder resection ishighly desirable.

Benign Prostatic hyperplasia (BPH) and prostate cancer are two of themost common urologic diseases that are treated with surgicalintervention in aging men. An estimated 50% of men have histologicevidence of BPH by age 50 years and 75% are thought to display suchevidence by age 80 years. In 40-50% of these patients, BPH becomesclinically significant. Although the incidence of uncontrolled bleedingfrom surgical intervention involving prostate and urethra is relativelylow, it remains a significant risk that must be addressed by in hospitalwith a length of stay over at least two to three nights. According tostatistical analysis of U.S. Department of Health and Human Service from2005 to 2010, there was an average of 150,000 discharges from eitheropen or transurethral procedure prostatectomy in the U.S., with directsurgery cost surpassing an average $4.5 billion annually. In thesepatients, the average length of hospital stay with open or transurethralprostatectomy was 3.1 and 2.4 days respectively. In the patients who hadblood transfusion due to significant blood loss (4-5%) in the surgery,the average length of stay was prolonged to five or six days that costan average $15,700 more in each case compared to the average cost($29,300) of prostatectomy patients in 2010. The costs of theprostatectomy procedure are high because of operating-room time, surgeontime, and hospital length of stay.

TURP is considered the benchmark therapy for BPH. Partial removal(resection) of the prostate is accomplished in TURP by minimallyinvasive surgery through the urethra using a cystoscope (endoscope forthe bladder via the urethra) and electrocautery. The thin loopelectrocautery used in TURP results in less tissue necrosis than otherless common minimally invasive prostatectomy procedures, however thereis more intraoperative bleeding with TURP. Appropriate prostateresection and control of bleeding in TURP, like other forms ofprostatectomy, are its essential challenges. The volume of theintraoperative bleeding in prostatectomy depends on the size of theprostate, the length of time to resect the prostate, and the surgeon'sskill. Significant bleeding or hemorrhage after prostatectomy oftencauses undesirable clot retention (and resulting urinary retention) inthe bladder and urethra that may prolong time in hospital, and evennecessitate re-operation. In general, arterial bleeding is easilyidentified and controlled by electrocoagulation, but the venous bleedingcommon in TURP is more difficult to control. Attempts to control venousbleeding by electrocautery and irrigation may result in undesirableoutcomes such as TURP syndrome. In standard of care control, venousbleeding is controlled by filling the bladder with irrigating fluid andapplication of an inflated transurethral balloon catheter to compressthe bleeding prostatic cavity. TURP associated post-operative morbidityrate has been reported as high as 18% with an operative mortality rateof 0.3%. In older patients, the risk of blood loss related morbidity andmortality increases significantly in association with coagulationdisorders and cardiovascular abnormalities. Uncontrolled bleeding duringTURP is still one of the major complications of prostate resection andthis often leads to converting to less desirable open surgery. Althoughthere is significant progress in the management of BPH, the incidence ofuncontrolled strong bleeding remains around 6% and blood transfusionrate to address this bleeding is 4% to 5%.

In the typical TURP, the length of hospital stay is two to four days andthe patient has an inflated urinary balloon catheter in place untilbleeding stops and urine becomes clear. Any significant reduction ofpost-op bleeding following TURP will shorten time of catheterization andhospital bed requirements. It will also decrease the incidence ofurinary tract infection, catheter-related patient discomfort and relatedcomplications. Significant hematuria (blood in urine), resulting fromeither transurethral or open surgery, which causes hemodynamicinstability and clot retention, requires immediate medical attention andmedical care for hemostasis, clot clearance, blood transfusion, andcoagulation evaluation. Treatment of significant hematuria through atransurethral approach is troublesome due to limited operative visualand spatial restriction. Most often the patient has to return to theoperating room to perform an open bladder surgery to achieve hemostasisand remove cystic clots. A complicating factor of prostatectomy is thatTURP patients are commonly anti-coagulated due to the presence of otherchronic conditions such as cardiovascular disease. Although it ispreferable to have these patients taken off their anti-coagulationmedication such as Coumadin and Plavix before TURP surgery because ofrisk of bleeding, it would be preferable to be able to perform theprocedure while the patient remains on their medication to reduce thepossibility of stroke or myocardial infarction during the procedure. Areliable and sustainable hemostatic technique, preferably effective inthe case of anti-coagulated individuals, is urgently required for thetransurethral application to control significant bleeding followingprostate resection.

BRIEF SUMMARY

The disclosure generally relates to delivery devices for deliveringand/or applying dressings, such as those including chitosan materials,into the bladder through the urethra. In some embodiments, a deliverydevice is used in connection with a TURP procedure.

In one aspect, the delivery device of the present disclosure generallyrelates to a chitosan endoluminal hemostatic dressing delivery deviceincluding a chitosan endoluminal hemostatic dressing (CEHD), a distalballoon, and a proximal balloon that is proximal along a length of thedelivery device with respect to the distal balloon, wherein the distalballoon, when inflated, can be used to position the proximal balloon andthe CEHD with low tension along the delivery device. In someembodiments, the chitosan endoluminal hemostatic dressing deliverydevice further includes a catheter. In some embodiments, the distalballoon, when inflated, can sit against a neck of a human bladder. Insome embodiments, the distal balloon, when inflated, can be used toalign the proximal balloon with an injury site. In some embodiments, theinjury site is at a prostate cavity injury. In some embodiments, theCEHD is attached to the proximal balloon by a releasable tape. In someembodiments, the CEHD is furled around the proximal balloon. In someembodiments, the proximal balloon can be inflated to deliver the CEHD toan injury site. In some embodiments, the chitosan endoluminal hemostaticdressing delivery device further includes a water impermeable sheathextending around the CEHD. In some embodiments, the water impermeablesheath can be ruptured before or upon delivery of the CEHD to an injurysite.

In another aspect, the present disclosure relates to a chitosanendoluminal hemostatic dressing delivery device including a CEHD, aballoon that can be used to deliver the CEHD to an injury site, and acatheter. In some embodiments, the injury site is inside a bladder of apatient. In some embodiments, the balloon can be aligned with the injurysite. In some embodiments, the injury site is at a prostate cavityinjury. In some embodiments, the CEHD is attached to the balloon by areleasable tape. In some embodiments, the CEHD is furled around theballoon. In some embodiments, the balloon can be inflated to deliver theCEHD to the injury site. In some embodiments, the chitosan endoluminalhemostatic dressing delivery device further includes a water impermeablesheath around the CEHD. In some embodiments, the water impermeablesheath can be ruptured before or upon delivery of the CEHD to the injurysite. In some preferred embodiments, the dressing is a CEHD andcomprises chitosan and the surface of the dressing facing inwardsagainst the balloon is preferably formed of non-modified, non-adhesivechitosan; meanwhile, the surface of the dressing facing out away fromthe balloon and towards the holding sheath and the tissue surface issubstantially modified to cause it to adhere uniformly to tissue onwetting and balloon inflation once the outer sheath has been removed.

A dressing used with the system of the invention may have one or more,or all, of the following features, such that it is: (1) able to befolded or furled and unfolded and unfurled without tearing orcompromised mechanical performance; (2) able to be applied in thepresence of blood and urine at about 37° C. without significantdimensional changes in length, width and height or loss in mechanicalproperties; (3) able to be delivered in the presence of urine and blood;(4) able to be delivered to injury site by a transluminal ortransurethral delivery device; (5) able to be unfolded or unfurled atdelivery site; (6) characterized by capillarity, porosity and absorbencythat is able to remove hydrophilic and hydrophobic biological fluidsthat can interfere with adhesion; (7) activated by wetting to adhere tobladder mucosa, resected bladder mucosa and resected prostate onapplication of uniform pressure; (8) able to contact itself andpackaging materials when dry without adherence to itself or topackaging; (9) inclusive of a tissue adherent side of dressing that isable to contact itself and packaging or delivery materials when wet withurine or blood without adherence to itself or to packaging/deliverymaterials if wet contact is not more than about 300 seconds, (10) ableto uniformly adhere to tissue and quickly stanch moderate to oozingbleeding at pressure ≤about 50 mmHg providing opportunity to allow TURPto be performed as an outpatient procedure; (11) able to be releasedfrom the delivery device to allow withdrawal of the delivery device fromthe urethra; (12) able to resist dissolution on exposure to urine atabout pH 4.5 to about pH 8 at about 37° C. in about the first 12 hoursof application; (13) enables (with or without delivery device in place)the urethra to remain patent with dressing or residues of dressingpresent and allows unobstructed passage of urine; (14) protects theinjury site and provides for promotion of healing; (15) provides acontrolled, slow degradation and/or dissolution from the attachment site(bladder neck, prostate, and/or urethra) to allow for removal withoutsurgical assistance in less than about 7 days. Dressings of the presentinvention may include catechol modified chitosan materials.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1A shows in-profile, a schematic drawing of a double ballooncatheter being used to deliver a dressing to a resected prostatic fossathrough a patient's urethra with maintenance of inflated bladder and itsirrigation by delivery of saline (H2O).

FIG. 1B shows a single balloon catheter being used to deliver a dressingthrough a patient's urethra to be applied at a resection injury of thebladder neck.

FIG. 1C shows a double balloon catheter being used to deliver a dressingthrough a patient's urethra to a resected prostatic fossa.

FIG. 1D shows a single balloon catheter being used to deliver a dressingthrough a patient's urethra to address injury and bleeding withanastomosis of the bladder neck.

FIG. 1E shows a preferred double balloon delivery catheter of theinvention with inflated distal balloon located inside a partially filledbladder with inflation of distal balloon rupturing the protective sheathdistally and along the distal seam of the sheath allowing the sheath tobe removed intact by pulling on its distal end.

FIG. 1F shows the double balloon catheter of FIG. 1E with the sheathfully removed and the furled dressing beneath revealed. The catheter ispulled gently from its proximal end to position the distal balloonagainst the bladder neck to provide for correct alignment of the moreproximal balloon (not shown) and the furled dressing (shown) against theresected prostatic fossa (shown in relief).

FIG. 1G shows the double balloon catheter of FIGS. 1E and 1F with theunsheathed and well-located proximal balloon inflated to apply andadhere the now unfurled dressing of the invention intimately against theresected prostatic fossa.

FIG. 2 demonstrates a photographic record sequence of images (FIGS. 2A,2B, 2C, 2D, 2E, 2F, 2G, 2H, and 2I) of preparation and attachment of aCEHD dressing of the invention onto a proximal balloon of a doubleballoon 14 French catheter.

FIG. 2A depicts a dressing being readied for attachment to the ballooncatheter with plan view of non-modified chitosan side inside foldedcone.

FIG. 2B depicts a dressing being readied for attachment to the ballooncatheter with side view of catechol-modified chitosan side outsidefolded cone and cone edge rim of non-modified chitosan.

FIG. 2C shows alignment of the tip of the balloon catheter (at top righthand of image) with base cone opening of dressing at bottom of image.

FIG. 2D shows tip of the balloon support inside the folded dressing.

FIG. 2E demonstrates furling the outlying wings of the folded dressingaround the balloon catheter.

FIG. 2F shows double sided pressure adhesive tape attachment of the apexof the folded cone of the dressing to the balloon catheter whilecontinuing to furl the loose wings of the dressing around the catheterbody.

FIG. 2G shows another view of FIG. 2F.

FIG. 2H depicts the placement and sliding of the tip of the ballooncatheter and attached furled dressing inside the protective sheath.

FIG. 2I shows the final furled dressing on its catheter with both passedalong the length of the protective sheath to its closed end. Theprotective sheath in the image is formed of a single seamed, tear-able,polypropylene tube about 8 mm in diameter, 32 cm in length, and 20microns in wall thickness, sealed at its distal end and reinforced alongits length with at least two 3 mm wide strips of non-tearable adhesivetape.

FIGS. 3A-3F demonstrate a schematic sequence of balloon catheter;circular, conical, folded chitosan endoluminal dressing including, forexample, a CEHD; attachment of chitosan dressing to balloon catheter;protection of catheter attached chitosan dressing by removable occlusivesheath; and positioning of catheter and dressing in urethra to coverprostate and bladder neck to enable delivery and attachment of dressingwith removal of catheter if desired.

FIG. 3A provides a schematic drawing of a double balloon cathetershowing three ports at its proximal end and 2 uninflated balloons at itsdistal end.

FIG. 3B provides a schematic drawing of a conical, partially foldedchitosan endoluminal dressing,

FIG. 3C provides a schematic drawing of a double balloon catheter loadedwith one circular chitosan endoluminal dressing, the circular chitosandressing of the invention folded into a cone shape, with the catheterpositioned through the clipped apex of the folded cone, and apexpositioned (and apex preferably attached to catheter by double sidedadhesive tape) proximally to the balloon filling so that the inside ofthe dressing cone extends over the collapsed underlying proximal balloonof the catheter. A single cylindrical sheath with closed end holds inplace and protects the underlying folded and furled chitosan dressing.

FIG. 3D presents an extended positioning of the catheter delivery deviceand its dressing with respect to position in urethra, prostate, bladderneck and bladder; with dressing overlap of the bladder neck and edge ofdistal balloon.

FIG. 3E presents preferred positioning of the dressing of the inventionon the balloon delivery catheter covering only the proximal balloon

FIG. 3F presents a preferred positioning of the catheter delivery deviceand its dressing as illustrated in FIG. 3E with respect to position inurethra, prostate, bladder neck and bladder.

FIG. 4 provides a schematic drawing of an alternate embodiment of thedelivery device and positioning of a chitosan endoluminal chitosanincluding, for example, a CEHD dressing of the invention.

FIG. 4A (the upper portion of FIG. 4 ) provides a schematic drawing of asingle balloon catheter loaded with two (2) chitosan endoluminaldressings of the invention, each folded into a cone shape, each withfolded edges of dressing in close approximation and extending toencompass the collapsed underlying single end balloon of the catheter. Asingle cylindrical sheath with closed end holds in place and protectsthe underlying folded and furled chitosan dressings. Also, a preferredpositioning of the catheter delivery device and its cargo dressing ispresented in FIG. 3A with respect to urethra, prostate, bladder neck andbladder.

FIG. 4B (the lower portion of FIG. 4 ) provides a schematic drawing ofaligned and partially folded chitosan endoluminal dressings of theinvention before cutting of their apex ends and before positioning,attachment and furling around the single catheter balloon of FIG. 3A andplacement of the overlying sheath.

FIG. 5 depicts a simple chemistry drawing of catechol chitosan reaction.

FIG. 6 depicts a chemical structure representation of chitosan (R1=H andacetyl radical) and catechol modified chitosan (R1=H, acetyl,hydrocaffeic acid radical, caffeic acid radical, trans-caffeic acidradical and Homoprotocatechuic acid radical). For chitosan polymer,preferably n>60, more preferably n>300, and most preferably n>600.

FIG. 7 depicts an N-acylation addition reaction in the presence of1-ethyl-3-(-3-dimethylamino-propyl)-carbodiimide (EDC) where3,4-dihydroxyhydrocinnamic is covalently attached to a chitosan C-2amine with a degree of substitution of 25% in aqueous solution at pH5.5.

FIG. 8 depicts oxidation of catechol modified chitosan to ortho-quinonemodified chitosan under elevated pH and in the presence of oxygen FIG. 9depicts Schiff base (A) and Michael addition (B) reactions causingcrosslinking between catechol modified chitosan and chitosan.

FIG. 10A and FIG. 10B depict digital images of the two-sided catecholmodified chitosan dressing of the invention adhered to the wall of a 250ml volumetric cylinder by balloon catheter application for 2 hourssubmerged in 0.9% w/w physiological aqueous saline solution at 25+3° C.at close to 48 hours after initial attachment. Note that there is notrace of the original unmodified chitosan dressing at 48 hours. FIG. 10Ais a side-on view and FIG. 10B is a plan view.

FIG. 11 depicts a digital endoscopic image of the catechol chitosandressing of the invention within 30 minutes attached uniformly to thebladder neck and lumen of urethra of a close to 100 lbs female swine.The bladder is swollen by urine and saline injected to aid in theviewing. The image was taken by trocar delivery of an endoscope throughthe wall of the swine bladder and with the endoscope viewport directedat the swine bladder neck and entrance to the urethra. The imagedemonstrates a patent urethra, a wispy rapidly degrading non-modifiedchitosan backing, and a modified catechol dressing intimately adhered tothe bladder neck and lumen of urethra.

FIG. 12 depicts a glass flow cell 4 cm long and 1.5 cm internal diametercapable of supporting a 6 cm long 1.5 cm diameter stretched tube ofporcine small intestine submucosa by wrapping over the ends of the celland applying pressure ties; i is glass jacket; ii is 4 cm; iii is 1.6cm; iv is glass fixture for tubing connection; v is perforated glasscylinder region between ring clamps; vi is ca. 3.2 cm; vii is 1.5 cm;viii is 1.5 cm; ix is (Schott) 1.5 cm ID; x is 2.5 mm tube wall.

FIG. 13 depicts a typical flow cell design (with 3 cells attached inparallel) for testing adherence and dissolution resistance under urineflow at 37° C. of novel dressings adhered to cell supported ex vivotissue surfaces.

FIG. 14 shows the mean bleeding rates in the bladder injury model of apreferred embodiment device of the invention (balloon and dressingcombined with delivery balloon deflated after application) compared tostandard of care control (balloon device without dressing but remaininginflated against injury).

FIG. 15 shows histological wound healing at 7 days of control andpreferred embodiment device of the invention.

FIGS. 16A-16G show tables of various parameters for batches used toprepare chitosan dressings.

FIG. 17A-17E show a table of various chitosan dressing preparations,including formulations, and dissolution, foldability, burst testing,ex-vivo, accelerated stability, and in vivo characteristics.

FIG. 18 depicts round-shaped catechol modified chitosan dressing thatare (pre-cut) 2.5 inches by 2 inches in diameter and compressed to near50 microns. The coloration of these catechol modified chitosan dressing,starting from left to right, ranges from light pinkish brown (firstdressing), 2 dressings of darker pinkish brown, 2 tan brown coloreddressings (no pink), 1 brown dressing and lastly 1 darker browndressing. Catechol chitosan dressings 5 and 6 are formed from 2.5 inchand 2 inch molds and they are backed with unmodified chitosan dressingsboth from 2.5 inch molds and the unmodified chitosan can be seen clearlyas the white halo (no brown or pink color) in dressing 6. The catecholchitosan and unmodified chitosan dressings were adhered together duringcompression to a final shared density >0.4 g/cm³. The pink coloration isassociated with unoxidized catechol while the brown color is associatedwith the oxidized catechol (o-quinone). The lighter browns and lighterpinks are associated with lower degree of substitution of the chitosanwith catechol (nearer to 10%) while the darker colorations (pinkishbrown and brown) are associated with higher degree of substitution ofthe chitosan with catechol (nearer to 20%).

FIG. 19 depicts a catechol modified chitosan dressing that has beenfolded and unfolded, while remaining intact, with visible fold axis(crease).

Reference numbers, if included in the Figures, correspond to writtentext as follows: 1—Side view of double balloon catheter (with bothballoons empty or collapsed); 2—Balloon catheter tubing body; 3—Proximalballoon (Delivery balloon); 4—Distal balloon (Distal orplacement/positioning balloon in a double balloon delivery catheter. Inone embodiment, the double balloon delivery catheter is preferred overthe single balloon catheter as the distal balloon can be used to ruptureand initiate removal of the sheath and it provides ideal ability tolocate the delivery balloon. The distal balloon may be used to achieveapposition of a dressing such as, for example, a CEHD, against thebladder neck in the case of anastomoses and bladder neck injury and, inthat case, the body of the dressing attached to the catheter extendsbeyond the proximal balloon and partly covers the bottom third of thedistal balloon); 5—Ports for the balloon catheter (three (3) ports aretypical in a two (2) balloon, or double balloon, delivery catheterhowever a multi-lumen catheter with two (2) balloons may have more).There is typically one port for each balloon and at least one point forirrigation and drainage. The ports typically connect to standard syringeluer connectors; 6—Irrigation ports (6 a proximal; 6 b distal);7—Expanded side view of the double balloon body and its collapsedballooned delivery end; 8-8 a is plan view of a conical, partiallyfolded dressing with attachment point (9); 8 b is side view of conical,partially folded dressing with attachment apex point (9); 8 c isconical, partially folded dressing with attachment point (9) proximal(left) of delivery balloon catheter. The apex end of the cone may beremoved by cutting to allow for matching with the diameter of thedelivery balloon attachment location or more preferably two short cutsare made at 900 to one another along opposing fold lines in the coneproviding for four or more short wings (10) of the conical dressing.Note that there may be two dressings on one balloon with distal andproximal attachment points (not drawn) or preferably one dressing withproximal attachment only. An alternate delivery embodiment is with thedressing furled as a cylinder around the delivery balloon (not drawnhere); 9—Apex attachment point of conical, partially folded dressing;10—Apex attachment wings of conical, partially folded dressing. Theattachment wings may be used to adhere the dressing to the ballooncatheter body to prevent its displacement from the original set positionon sliding application of the overlying protective sheath. The shortwing attachment points can become sufficiently weakened followingwetting in dressing delivery that deflation of the balloons and a simpletwist allow for removal of the balloon catheter leaving the dressingattached firmly and uniformly inside the lumen of the urethra;11—Adhesive attachment point of dressing to balloon delivery catheter.Preferably double sided adhesive tape is used to adhere 10 to ballooncatheter body; 12—Fully folded and furled dressing (8) attached to thedelivery balloon of the delivery catheter; 13—Side view of deliverycatheter with fully folded and furled dressing (8) with length of fullyfolded and furled dressing extending to partially overlap with distalpositioning balloon to enable placement by distal balloon tractionagainst bladder neck; 14—Occlusive, cylindrical sheath with sealeddistal end (14 b) to keep the dressing in place during delivery and tomaintain the dressing dry and free of potential sources of contaminationduring delivery. The sheath is removed by partial distal end rupture andwithdrawal removal intact from proximal end (14 a) after rupture;15—Balloon catheter positioned desirably against resected prostate andbladder neck to deliver longer 12; 16—Urethra; 17—Prostate; 18—Bladder;19—Bladder neck; 20—Side view of delivery catheter with fully folded andfurled dressing (8) with shorter length (in comparison to 13) of fullyfolded and furled extending only to distal edge of proximal deliveryballoon and no overlap with distal positioning balloon to provideplacement by proximal delivery balloon alone; and 21—Balloon catheterpositioned desirably against resected prostate and bladder neck todeliver shorter 12 (in comparison to 15).

DETAILED DESCRIPTION

The present invention addresses rapid bleeding control in transurethralprostatectomy, open prostatectomy, bladder resection using systems fordelivery and application of a foldable, thin (thickness ≤about 500microns), tissue adherent, dressing. Dressings suitable for use with thepresent invention include, for example CEHDs and may comprise catecholmodified chitosan.

The current invention provides: (1) an ability to rapidly controlhemorrhage in prostatectomy using a noninvasive procedure; (2) anability to control bleeding in anti-coagulated patients; (3)significantly reduced patient pain and discomfort by control of bleedingwithout need for prolonged catheterization; (4) significantly reducedhospital length of stay; (5) significantly reduced healthcare cost; (6)significantly reduced rate of morbidity; and (7) trending outcomes to areduced rate of mortality.

A dressing used with the system of the invention may have one or more,or all, of the following features, such that it is: (1) able to befolded or furled and unfolded and unfurled without tearing orcompromised mechanical performance; (2) able to be applied in thepresence of blood and urine at about 37° C. without significantdimensional changes in length, width and height or loss in mechanicalproperties; (3) able to be delivered in the presence of urine and blood;(4) able to be delivered to injury site by a transluminal ortransurethral delivery device; (5) able to be unfolded or unfurled atdelivery site; (6) characterized by capillarity, porosity and absorbencythat is able to remove hydrophilic and hydrophobic biological fluidsthat can interfere with adhesion; (7) activated by wetting to adhere tobladder mucosa, resected bladder mucosa and resected prostate onapplication of uniform pressure; (8) able to contact itself andpackaging materials when dry without adherence to itself or topackaging; (9) inclusive of a tissue adherent side of dressing that isable to contact itself and packaging or delivery materials when wet withurine or blood without adherence to itself or to packaging or deliverymaterials if wet contact is not more than about 300 seconds, (10) ableto uniformly adhere to tissue and quickly stanch moderate to oozingbleeding at pressure ≤about 50 mmHg or, for example, a bleeding rate ofbetween about 20 ml/min to about 150 ml/min or greater, providingopportunity to allow TURP to be performed as an outpatient procedure;(11) able to be released from the delivery device to allow withdrawal ofthe delivery device from the urethra; (12) able to resist dissolution onexposure to urine at about pH 4.5 to about pH 8 at about 37° C. in aboutthe first 12 hours of application; (13) enables (with or withoutdelivery device in place) the urethra to remain patent with dressing orresidues of dressing present and allows unobstructed passage of urine;(14) protects the injury site and provides for promotion of healing;(15) provides a controlled, slow degradation and/or dissolution from theattachment site (bladder neck, prostate, and/or urethra) to allow forremoval without surgical assistance in less than about 7 days.

As used herein, bladder mucosa is broadly defined to include any exposedtissue surface in the bladder including any other tissue surface exposedby way of an operation (e.g., surgical operation such as TURP). Bladdermucosa therefore includes bladder mucosa naturally present in thebladder, resected bladder mucosa, and resected prostate, etc.

Chitosan endoluminal hemostatic dressing (CEHD), as used herein, refersto a chitosan dressing that is hemostatic, and can be used in anendoluminal area e.g., inside bladder. CEHD is not limited by theposition of its application and includes chitosan dressings applied atany location inside a human body including, but not limited to, bladdermucosa.

Bleed rates, or blood flow rates, in ml/min suitable for treatment bythe devices described herein may range from about 1 ml/min to about 200ml/min. In preferred embodiments, the bleeding rates addressed by thedevices range from about 1 ml/min to about 150 ml/min. A bleed rate ofbetween about 20 ml/min and 25 ml/min is considered “brisk” bleeding.Oozing bleeding is generally greater than about 1 ml/min as it is notedthat low bleeding rates such as 1 ml/min typically clot and stop oftheir own accord unless the subject is on anticoagulation therapy or hasa disorder of the clotting cascade due to reasons other than takinganticoagulation medication. For such a subject with irreversibleanticoagulation medication or with a bleeding disorder, 1 ml/min oozingbleeding remains concerning and needs to be addressed such as by thedevice of the invention. In some embodiments, the devices describedherein are used to address TURP bleeding rates of between about 1 ml/minand about 25 ml/min, or about 1 ml/min and about 20 ml/min, or about 1ml/min and about 15 ml/min, or about 1 ml/min and about 10 ml/min, orabout 1 ml/min and about 5 ml/min.

A TURP delivery device may include any device that is used in a TURPprocedure or any device used in connected with a TURP procedure.

Dressings

Dressings suitable for delivery using the systems described herein mayinclude, but art not limited to, for example, chitosan based materialsor catechol modified chitosan based materials. Such dressings may bereferred to as CEHDs.

Chitosan dressings may refer to compositions that include varyingamounts of chitosan. General chemical compositions and different formsof a chitosan dressing are described, for example, in U.S. Pat. Nos.7,820,872, 7,482,503, 7,371,403, 8,313,474, 7,897,832, 9,004,918,8,920,514, 9,204,957, 8,741,335, 8,269,058, 9,205,170, and 10,086,105.Such chitosan dressings, due to their chemical and physical propertiesas described previously, have been used to stop bleeding.

In preferred embodiments of the present invention, dressings comprise acatechol modified chitosan material. Reference to catechol-modifiedchitosan may include reference to catechol-added chitosan. Catecholchitosan materials are further described below.

The chitosan used herein preferably comprises the non-mammalian materialpoly[β-(1→4)-2-amino-2-deoxy-D-glucopyranose. The chitosan can beprocessed in conventional ways from chitin obtained, for example, fromanimal crustacean shells such as shrimp. Chitosan may be biocompatibleand biodegradable within the body, and is capable of being broken downinto glucosamine, a benign material.

A chitosan dressing can be dry or wet. A chitosan dressing is “dry” ifthe moisture content in the chitosan dressing is less than about 15% byweight, preferably about 10% by weight, and more preferably about 5% byweight. A chitosan dressing is “wet” when the chitosan dressing has comein contact with a source of water, including water in a physiologicalenvironments and biological fluids, or in an aqueous solution. Forexample, a chitosan dressing becomes wet when the chitosan dressing, asdescribed in this disclosure, comes in contact with urine or blood or abladder tissue surface (bladder mucosa). The chitosan dressing,remaining substantially in a solid form absorbs, displaces, redirects orchannels water/moisture in the physiological environment of bladdermucosa in amounts sufficient to permit adhesion of the chitosan dressingto the tissue surface. The adhered chitosan dressing can be used to sealwound surfaces and slow or stop further bleeding.

Bladder fluid and bladder fluids are used interchangeably in the presentdisclosure. Bladder fluids may include urine or other types ofphysiological fluids present in the bladder, and may additionallyinclude blood.

In a preferred embodiment, the chitosan endoluminal hemostatic dressing(CEHD) of the invention contains preferably greater than or equal to 25%by weight chitosan; more preferably greater than or equal to 50% byweight chitosan and most preferably greater than or equal to 75% byweight chitosan. Chitosan is a generic term used to describe linearpolysaccharides that are composed of glucosamine and N-acetylglucosamine residues joined by β-(1-4) glycosidic linkages (typicallythe number of glucosamines ≥N-acetyl glucosamines) and whose compositionis soluble in dilute aqueous acid (Roberts 1991). The chitosan familyencompasses poly-β-(1-4)-N-acetyl-glucosamine andpoly-β-(1-4)-N-glucosamine with the acetyl residue fraction and itsmotif decoration (either random or block) affecting chitosan chemistry.The C-2 amino group on the glucosamine ring in chitosan allows forprotonation, and hence solubilization of chitosan in water (pKa≈6.5)(Roberts 1991). Other hydrophilic polymers such as, for example, guar,pectin, starch and polyacrylic acid may be used.

In a preferred embodiment, the dressing of the invention is polymeric,thin (preferably dry dressing thickness of about ≤500 microns, morepreferably thickness of about 200 microns or about ≤100 microns, mostpreferably thickness of about ≤150 microns), flexible, porous, dry,biocompatible, tissue adherent and hemostatic. In some embodiments, thedressings are about 100 to about 150 microns in thickness, and suchdressings may comprise a bilayer dressing of two about 70 micron layers(one layer that is adhesive and resistant to dissolution and one layerthat is straight chitosan) with sum thickness nearer 150 microns ondelivery.

The dressings are not limited in shape; however square, rectangular,circular, or circular petal shaped dressings are preferred. In oneembodiment, a maximum size could be up to about 70 mm×70 mm square or 70mm in diameter. In another embodiment, dressing size could be about 65mm×65 mm square or 65 mm in diameter, 60 mm×60 mm square or 60 mm indiameter, 55 mm×55 mm square or 55 mm in diameter, or 50 mm×50 mm squareor 50 mm in diameter, 45 mm×45 mm square or 45 mm in diameter, 40 mm×40mm square or 40 mm in diameter, 35 mm×35 mm square or 35 mm in diameter,30 mm×30 mm square or 30 mm in diameter, or 25 mm×25 mm square or 25 mmin diameter, etc. In still another embodiment, each of the length andwidth may range from about 20 mm to about 70 mm, or from about 20 mm toabout 60 mm in diameter. As dressings become larger in size they becomeincreasingly subject to delivery limitations in confined cavities.

In another preferred embodiment, the dressing is delivered by ballooncatheter, and the dressing has a diameter size of about around 5 cm, or7 cm maximum. The balloon catheter is preferably passed through acentral small hole (about same diameter as catheter balloon which isgenerally about 4 mm to about 7 mm diameter, or the hole can be larger,e.g., up to 12 mm) in the dressing and the dressing (dressing 30 mm to70 mm diameter) is adhered to the catheter tubing (same diameter ascatheter) opposite the balloon by small dressing tabs either side of thehole. In some embodiments, the surface area change in the dressing froma folded, furled, closed or compact condition is about ⅛ of the surfacearea when the dressing is in an unfolding, unfurled, or uncompactedcondition. Dressings described herein may provide a large dressingsurface area in an open, unfurled, or unfolded condition. Alternatively,dressings described herein may provide a small dressing surface are in aclosed, compact, furled, or folded condition. The ability of thedressings to be folded, furled, or closed allows them to be more compactand protected for delivery and reduces the likelihood that the dressingsurface is prematurely wetted prior to delivery to a target tissuetreatment site.

In a preferred embodiment, the dressing is about 100 microns thick, isabout 5.0 cm in diameter, and will have an open, unfurled, or unfoldedoutward facing surface area of about 38.66 cm². On the balloon deliverydevice, a closed, compact, furled, or folded dressing 3.0 cm diameterdressing will have an outward-facing cylindrical surface area (in a 2.5cm long cylinder) of about 5.09 cm² on a 7 mm diameter catheter balloon,and 1.85 cm² closed on a 4 mm diameter catheter balloon, but will have asurface area of about 14.0 cm² in an open, unfurled, or unfoldedcondition. Thus, in one example, a dressing of the present inventionmay, in an open, unfurled, or unfolded condition, have an outward facingsurface area that is about eight (8) times greater than the outwardfacing surface area of that same dressing when it is in a closed,furled, or folded condition. In some embodiments, the ratio of theoutward facing surface area of an open, unfurled, or unfolded to aclosed, furled, or folded dressing is about 15:1, or about 14:1, orabout 13:1, or about 12:1, or about 11:1, or about 10:1, or about 9:1,or about 8:1, or about 7:1, or about 6:1, or about 5:1, or about 4:1, orabout 3:1, or about 2:1.

It is noted that the most common catheter balloon used with a deliverydevice in TURP is 0.4 cm diameter (4.0 mm) and hence this is the mostpreferred size for the dressing delivery. Alternatively, a morepreferred size is 0.5 cm diameter, which is a standard catheter diameterfor a TURP delivery device but less common than the 0.4 cm catheter.Another preferred catheter diameter size of a TURP delivery device isbetween 0.5 cm and 0.7 cm which is more a custom channel size and, thus,less common than the 0.4 or the 0.5 cm catheter diameter size.

A dressing as described herein is able to be folded and unfolded, is notreadily soluble in blood or body fluid, such as urine, at about 37° C.within, preferably, the first 6 hours of application, more preferablythe first 12 hours of application, and most preferably the first 24hours of application, and degrades and/or dissolves fully in contactwith bladder fluids at about 37° C. within about 7 days.

A dressing as described herein will not adhere to the delivery device,and does not swell or shrink appreciably, i.e., it does not increase ordecrease in size by more than about 25% in length and width, or morethan about 50% in thickness, in the presence of blood and urine at about37° C.

In a preferred embodiment, the dressing may be terminally sterilizedwithout affecting dressing characteristics. When it is stored undercontrolled conditions in its packaging at room temperature of about 21°C. to about 25° C., its tissue adhesion properties, mechanicalproperties, dissolution properties in bladder fluids, swellingproperties, and hemostatic properties are stable and do not changeappreciably over time (e.g., about ≤2 years).

A preferred embodiment, the dressing has a tissue adhesive side and anon-adhesive side. In this embodiment, the non-adhesive side may providea surface that when wet readily slides away from itself and from anyapplicator or delivery device surface that is applying pressure againstthe dressing inside a lumen, and/or in the bladder.

A preferred embodiment of the dressing is that it is formed of asubstantially dry chitosan composition with a water content of about≤15%, or about ≤8%. The dry chitosan composition is preferably formedusing phase separation and drying of an aqueous solution of chitosan andwater. The dry chitosan dressing is preferably prepared in sheet formwhich may be cut to size.

Preferred embodiments of the biocompatible, bio-dissolvable, tissueadherent chitosan dressing are able to resist dissolution in bladderfluid and blood at about 37° C. for at least about 6 hours is tissueadherent and includes materials and material structures that promoteresistance to rapid dissolution and degradation in urine of the bladder.This is a significant advantage of the chitosan dressings disclosedherein.

Chitosan dressings provided herein can be applied to a mucus surface,e.g., in the bladder by light pressure, or pressure of up to hundreds ofkPa. Light pressure applied to the dressing on a tissue surface as usedherein indicates a pressure that attaches and keeps a chitosan dressingin contact with an injury site without significant deflection ormovement of the tissue so as to allow the chitosan dressing, through itscompositional structures and characteristics, to interact to promoteadherence with the injury site to stop bleeding. In some embodiments, alight pressure is a pressure at about most preferably 10 kPa or less,more preferably 25 kPa or less, or preferably 50 kPa or less (note 100g/cm2=9.8 kPa). In TURP, pressure can be applied for, typically, three(3) mins to 180 mins since the balloon can be pressurized and left inplace.

Production of Chitosan Dressing

The chitosan dressings of the present invention may be generated usingvarious methods and processes. In some embodiments, the chitosandressing may be formed by freeze phase separation and drying. In analternate embodiment, the dressing is formed by addition of a foamingagent to provide a low density foam before freezing followed by drying.Freeze phase separation followed by removal of frozen solvent bysublimation is called freeze drying. Freeze phase separation is aprocess of solidification from dilute solution whereby removal of heatand resultant lowering of temperature through a container or moldsurface holding the dilute solution results in a localized solid crystalnucleation of pure solvent and subsequent propagation and growth of puresolvent crystal. A result of the pure solvent crystal growth in a dilutesolution is that solute diffuses away from the growing crystal front tosolidify at the interstices between the growing crystal. Freeze phaseseparation of dilute polymer aqueous solutions results in alternatelayers of thin polymer lamella between thicker layers of ice. Removal ofthe ice by methods which do not disrupt the polymer lamella results in alow-density polymer dressing with inter-connected porous structure. Forexample, in one embodiment, low-density polymer dressings may have aninitial dressing density from about 0.005 g/cm³ to about 0.05 g/cm³.

In an alternate embodiment, the freeze phase separated dressing isformed by freezing of a foamed dilute solution followed by drying. In analternate embodiment, the dressing is formed by non-woven fiber spinningprocesses, such as centrifugal spinning, electrospinning or solventfiber extrusion into a coagulation bath. In yet another alternateembodiment, the dry dressing of the invention may be formed from a wovenfiber process. In yet another alternate embodiment, the dry dressing ofthe invention may be formed by phase inversion and precipitation with anon-solvent (as is typically used to produce dialysis and filtermembranes). In still another alternate embodiment, the dressing of theinvention may be formed from an additive 3D printing process.

In a preferred embodiment of the invention, the dressing preparationprocess may include a compression process that changes the initialdressing density from an initial preferred range of about 0.005 g/cm³ toabout 0.05 g/cm³ to a final preferred range of about 0.03 g/cm³ to about0.7 g/cm³; however, ranges of about 0.08 g/cm³ to about 1.2 g/cm³ arealso contemplated. It is noted that a density of about 1.5 g/cm³ is thedensity of void-free chitosan dressings. The compression process mayinclude application of temperature in the range of about 20° C. to about150° C. To avoid substantial dressing swelling of the dry compresseddressing on contact with biological fluid, the temperature of thecompression is preferably applied by a method that may include but notbe limited to convection, conduction and radiation, and the temperatureof the compressed dressing should preferably be maintained at leastabout 80° C. for at least about 15 seconds.

Heat during compression is a tool that allows plasticization and moldingof the chitosan without cracking or tearing of the chitosan(non-destructive molding). The first glass transition temperature (Tg)of pure dry chitosan is near 80° C. which if processed near in the caseof pure dry chitosan will allow ready non-destructive molding of thechitosan as well as some crystalline annealing of its structure. It ispossible to lower the Tg by application of plasticizers such as water orglycerol to the chitosan and hence provide a similar level ofnon-destructive molding at lower temperature. Here, it is noted thatchitosan can be molded non-destructively in the range 20° C. to 150° C.Outside of this range it would still be possible to non-destructivelymold the chitosan but much more difficult. Above 150° C. the chitosanbegins to thermally degrade while below 20° C., the addition ofplasticizers may lead to undesirable loss of chitosan crystallinitywhich provides for dissolution resistance and resistance to degradativeprocesses such as occur in sterilization.

Preferably, the compression prevents substantial swelling of the drycompressed dressing on contact with biological fluid and is performedwith moisture content of the dry dressing during the compression atabout ≤15% w/w. The compression may be applied through twin ormulti-roller compression and/or uniaxially between adjacent platens.

The compression may be against a uniform flat or curved surface toprovide a smooth finish to the compressed dressing.

Alternatively, the compression may be applied against an etched,machined, ablated or other type of surface treatment that imparts adepleted or added surface texture. The surface texture may be a randomor it may be a regular repeated pattern. The pattern of the surface mayassist in folding and unfolding or furling and unfurling the dressingand may provide for hinge-like properties in the dressing. Such texturemay be used as an adjunct to quickly lock the dressing in place and stopit moving when applied. Movement of the surface of the dressing whilepositioned against the target tissue surface can cause filming and henceclosure of the open surface structure which can lead to loss ability toremove anti-adhesive biological fluid at the surface and hence loss ofability to adhere the dressing to the surface. The timescale of thechanges occurring at the dressing surface is very important such thatsurface uptake of fluid with significant surface dressing channelclosure is highly undesirable. A good way to avoid such movement is tophysically fix the dressing in place as soon as it contacts the tissuesurface.

Prior to the present invention, thin solid chitosan dressings weregenerally rigid, not flexible enough to be bent or folded or furledwithout breaking, fracturing, or otherwise losing their intact shape orbecoming otherwise unsuitable for use. Chitosan dressings providedherein, due to their compositional structures and characteristics, canbe folded and unfolded along a folding axis while still being intact andsuitable for use in stopping bleeding. Interestingly, and contrary toexpectation, it has been found that chitosan dressings described herein,when folded, become less resistant to tearing or breakage along theirfolded seams. In some embodiments, the chitosan dressing providedherein, due to its compositional structures and characteristics, can befurled without losing its compositional structures and characteristicsand still being intact and able to stop bleeding. In some embodiments,the chitosan dressing provided herein, therefore, is able to bedelivered by balloon catheter along the urethra while still maintainingtheir compositional structures and characteristics intact. Exemplarydiameters of the balloon catheter supporting the chitosan dressing caninclude a diameter of about 12 mm or less, and including, but notlimited to, 3 mm, 3.5 mm, 4.0 mm, 4.5 mm, 5.0 mm, 5.5 mm, 6.0 mm, 6.5mm, 7.0 mm, 7.5 mm, 8.0 mm, 8.5 mm, 9.0 mm, 9.5 mm, 10.0 mm, 10.5 mm,11.0 mm, 11.5 mm, and 12.0 mm.

Catechol Modified Chitosan; and its Production

The chitosan dressings described herein relate to chitosan dressingscomprising catechol modified chitosan and/or hydrophilic polymers. Otheraspects of chitosan dressing comprising catechol modified chitosan aredescribed in more details below.

Preferred embodiments of the chitosan endoluminal hemostatic dressing(CEHD) of the invention include compositions with catechol modifiedchitosan and/or, optionally, other hydrophilic polymers. Preferably thecatechol modified chitosan in the dressing provides prolonged adherenceto wetted tissue with tissue adherence ≥about 1 kPa resistingdissolution in water, saline solution, blood and/or bladder fluid atabout 37° C. for ≥about 6 hours. Preferably the catechol modifiedchitosan is formed by N-acylation of the C-2 amine on the chitosanglucosamine by 3,4-dihydroxyhydrocinnamic acid (alternatively named3-(3,4-Dihydroxyphenyl)propionic acid, Hydrocaffeic acid)).Alternatively, the chitosan N-acylation to produce a catechol modifiedchitosan may include but not be limited to a modification with one of a3,4-Dihydroxycinnamic acid (caffeic acid); a trans-3,4-Dihydroxycinnamicacid (trans-caffeic acid); and a 3,4-Dihydroxyphenylacetic acid (DOPAC,Homoprotocatechuic acid).

The presence of catechol in the composition provides for somepoly-conjugated structure as the catechol is oxidized to o-quinone. Thiscauses visible difference between the unmodified chitosan and catecholmodified chitosan compositions, which may be off-white or pink to darkbrown in color, respectively. It is noted that the catechol modifiedchitosan compositions go from pink to brown when oxidation occurs in thecatechol.

Pink coloration in the catechol modified chitosan, signifyingsubstantial absence of crosslinking, is provided in the aqueoussynthesis by maintaining pH reaction solution at or below pH 5.5. Thepink coloration may also be provided in the aqueous synthesis byperforming the modification and subsequent processing stepssubstantially in the absence of oxygen such as by using aqueous systemspurged with an inert gas which may include but not be limited to argonor nitrogen. Although the pink coloration may not be desirable in thefinal solution or catechol modified product, it may be desirable inintermediate handling stages (such as immediately after chitosanderivatization with catechol and/or dialysis and/or washing of thesubsequent catechol chitosan solution to remove residual unreactedmaterial) because it allows for stable dry product polymer storage anddry product weight determination with subsequent ability tosubstantially re-dissolve the pure dry catechol modified product inwater to a desired dry weight at a later time. This water-solublechitosan catechol material is then subsequently oxidized and crosslinked(with brown coloration). However catechol modified chitosan which isdried before oxidation is not suitable for use in the chitosan dressingof the invention because dressings including such treated catecholmodified chitosan are not readily redissolved and the final solutionincludes an undesirable mass fraction (>5% w/w) of insoluble particulate(>10 microns in diameter). Additionally catechol chitosan prepared afteran intermediate freeze drying stage is more prone to early dissolution.It is noted that too much crosslinking in TURP (i.e., brown color) isless desirable as this makes the dissolution in urine take longer, forexample, longer than 168 hours when the target complete dissolution isbetween about 72 hours to about 168 hours).

In a preferred embodiment, the catechol modified chitosan is not removedfrom solution by an intermediate drying step to allow for storage butrather it is kept in aqueous solution and oxidized in aqueous solutionby exposure to higher than about pH 5.5 in the presence of atmosphericoxygen. Preferred pH control is achieved by adjustment of partialpressure of aqueous dissolved carbon dioxide (increased partial pressurereduces pH while decreased partial pressure increases pH to nearer pH7). An alternative preferred means of pH control is by incrementaladdition of a strong acid to lower pH and a strong base to raise pH.Examples of strong acids may include, but are not limited to,hydrochloric acid, sulphuric acid and nitric acid. Examples of strongbases may include but not be limited to sodium hydroxide and potassiumhydroxide. Subsequent drying of this aqueous water-soluble oxidizedcatechol modified chitosan results in a preferred level of crosslinkingof the catechol chitosan with good resistance to dissolution anddegradation in the bladder. The catechol chitosan solution may bediluted by addition of water or concentrated by water removal. The watermay be removed by the techniques including, but not limited to,ultrafiltration, reverse dialysis and centrifugation. The solid fractionof the solution may be determined by sampling a known volume from thesolution and performing analyses including but not limited togravimetry, fourier transform infrared spectroscopy, ultraviolet-visiblespectroscopy, refractometry, and pycnometry.

In a preferred embodiment, the catechol modified chitosan composition isof a brown color resulting from catechol oxidation to o-quinone. Thequinone is produced by autoxidation of the catechol hydroxyls in thepresence of oxygen and at pH above about 5.5. Schiff base reaction ofquinone with chitosan C-2 amine produces crosslinking in the modifiedchitosan. The color of the catechol modified chitosan composition iscontrolled during synthesis by controlling pH and oxygen exposure.Maintenance of pH at or below about pH 5.5 inhibits the production ofo-quinones. Subsequent conditioning of dialysis solution, final washed,or dialysed catechol chitosan solutions in a preferred pH range 5.8 to6.2 provides for more dissolution resistant, darker, more oxidizedcatechol. In some embodiments, the coloration of catechol modifiedchitosan characterizes one aspect of the catechol modified chitosandressing. In some embodiments, the coloration reflects the degree ofsubstitution of the chitosan with catechol. In some embodiments, thecoloration from pink to brown correlates with the degree ofsubstitution. FIG. 16 shows exemplary embodiments of differentcolorations reflecting and correlating with different degree ofsubstitution of the chitosan with catechol.

In order to prepare a dry dressing from the catechol chitosan, apreferred light brown to darker brown catechol aqueous chitosan solutionis prepared which may be used by itself or may be mixed with otheraqueous hydrophilic polymer solutions including but not limited tosolutions of chitosan and/or, optionally, hydrophilic polymers.Preferably, the dry phase separated catechol chitosan dressings areprepared as densified dried freeze-phase-separated and fibrous dressingstructures.

Preferred crosslinked catechol modified chitosan compositions of theinvention provide good tissue adherence and 10 times to 100 timesincreased resistance to dissolution in the bladder compared to dressingsformed substantially of unmodified chitosan. For example, FIGS. 6A, 6B,and 6C show dissolution testing results demonstrating that chitosandressings are gone in 15 minutes while some catechol dressings lastedgreater than 24 hours. The catechol modified chitosan compositionsdescribed herein, provide hitherto unknown longevity, biocompatibility,and ability to eventually dissolve.

Preferred rapid adherence to bladder mucosa of the chitosan endoluminalhemostatic dressing (CEHD) of the invention (≤1 minute) is provided inthe dry chitosan dressing by the promotion of quaternary ammonium cationformation at the chitosan glucosamine C-2 amine by the presence of anacid in the dry dressing composition. Preferred chitosan acid salts inthe dressing may include salts of acetic, lactic, glycolic, citric,succinic, malic, hydrochloric, glutamic, ascorbic, malonic, glutaric,adipic, pimelic, and tartaric acids, and combinations thereof.Preferably the acid salt % weight of the chitosan is greater than about2% and less than about 15%. To achieve fast adherence (e.g., ≤1 minute)to wet tissue, the moisture in the dry bladder dressing is preferablyless than about 15% by weight; more preferably it is less than about 10%by weight and most preferably it is less than about 5% by weight.

In the case of densified freeze-phase-separated and dried chitosandressings, the chitosan solution is poured into thefreeze-phase-separation mold (typically in the shape of a pan with ahorizontal flat base) with preferably around a 0.1% w/w, more preferablyaround 0.5% w/w and most preferably 0.25% w/w hydrophilic polymerchitosan solution. The hydrophilic polymer solution is preferably addedto the horizontal flat pan to a vertical depth of preferably about 10mm, more preferably 2.5 mm and most preferably 5.0 mm mold depth. Thesolution in the mold is subsequently frozen and dried to remove water bysublimation or freeze phase substitution (solvent extraction of the icewith a non-solvent to the polymer) to a low density (>99% void volume)open or porous dry sponge with a dry density <about 0.01 g/cm³ (or, forexample, about 0.005 g/cm³ for a catechol chitosan uncompressed dressingfrom 0.5% solution, which is about ⅕ or 20% of the density of anuncompressed HemCon Bandage chitosan sponge, which is about 0.025g/cm³). Lyophilization is typically performed at pressure below 300mTorr while freeze substitution involving a dry, cold (e.g., <−20° C.)solvent such as ethanol is performed at atmospheric pressure. The drysponges are then compressed, preferably to greater than about 0.4 g/cm³density and less than about 100 microns thickness. The preferredcompression is not limited to but may include uni-axial compressionbetween aligned flat platens, wherein the platens are heated between 18°C. and 150° C. and are pressure loading up to 10,000 bar.

The preferred compression creates a remarkably thin (e.g., range fromabout ≤50 microns to about ≤200 microns) strong (e.g., 5 MPa to 25 MPaUTS) readily foldable chitosan dressing that may be placed minimallyinvasively anywhere in the body in a confined folded form that can bereformed without compromised performance to the original unfoldeddressing form for accurate and effective high surface area placement andattachment.

Foldability is addressed in the examples below. In one embodiment, foldtesting involved folding the horizontally planar final compressedcircular dressing through 180° edge over edge, first in an anticlockwisedirection, holding the edges together and compressing firmly in themiddle of the dressing to create a single linear fold axis (or crease)in the dressing. The folded dressing is then opened and the edge to edgefold is reproduced in the new fold axis but with the folding in theopposite clockwise direction. Foldability success can be rated as notears or cracks being visible along the fold axis and no significantloss in tensile properties of the dressing (determined by gentle pullingacross the fold of the dressing). FIG. 17 shows a catechol modifiedchitosan dressing that has been folded and unfolded, remaining intact,with visible fold axis (crease).

Freeze phase separation of dilute aqueous polymeric solutions results inphase separation of micron and submicron thin polymeric chitosan lamellainterspersed regularly between ice crystal sheets close to 200 micronsin width. Removal of the ice by sublimation (freeze drying) oralternatively by solvent extraction leaves the dry sponge composed ofclose-to-aligned, thin (≤1 micron), polymeric chitosan lamella.Compression of the polymeric chitosan lamella at close to or greaterthan their glass transition temperature (Tg for dry chitosan is near 80°C.) allows for their compression into the thin (near 50 microns) densepolymeric structure formed of layers of hundreds of strong compliantpolymeric chitosan leaves (lamella) which do not readily propagatecracks and which can be folded repeatably without failure. Suchmulti-leaf layering achieves remarkable strength. Prior to the presentinvention, no one has previously investigated high-densityfreeze-phase-separated chitosan dressings for manufacture and use asdescribed herein and with the aim to address key problems solved by thepresent invention such as, for example, adhesion by removal ofinterfering fluids (by absorption, channeling, displacement, and/orre-direction), ability to form a fold axis and ability to resistmechanical failure on repeated folding and unfolding along the foldaxis.

In one embodiment, porosity (void space >99%) is complete anduninterrupted in the non-compressed dressing with pore size range of20-300 microns with substantially most of the pores near 100-200microns. The un-interrupted pore structure is indicated in thecompressed dressings by their ability to absorb biological fluid such asblood.

In some embodiments, crack free, clean edge holes near 500 microns indiameter may be formed in the dressing after compression by localizedapplication of narrow gauge (near 500 microns in diameter), sharppointed needle through the dressing and into a flat, hard elastomericsurface applied immediately against the dressing which may receive andrelease the point of the needle. Preferred receiving support flatsurfaces include but are not limited to clean, dry thermoplasticelastomers with Shore 55D to 90D in hardness. Alternative methods ofhole formation may include but not be limited to use of a small diameter(near 500 microns) hole punch or a laser cut hole.

In some embodiments, chitosan dressing provided herein has holes in thedressing. In some embodiments, the holes receive fiber or otherreinforcing attachment elements. Such a reinforcing element may beformed by simple local application of a reinforcing fluid to locallybind with the edges of the holes. A reinforcing fluid used in thedevelopment of the present invention included cyanoacrylate glue whichbound the compressed chitosan lamella of the dressing together andprevented local delamination and fibrillation of the chitosan at thehole stress point. Another embodiment of a hole reinforcing element ismicro-molded interlocking parts of plastic or metal (dissolvable in thebladder or alternate area in the body of application) that are placed onone side of the hole and the opposite hole side to permanently fittogether and be able to support load through the hole without causingdressing delamination, fibrillation or other stress related failure atthe dressing hole when loaded. In some embodiments, the micro moldedparts may include the part on the side of the attachment to a deliverydevice that enables convenient snap-on attachment and snap-offdetachment of the dressing to the delivery device.

As used herein, the term fold axis is intended as part of the dressingsheet which demonstrates memory in the material of bending stress and orfolding and is typically localized to narrow regions of high bendingstress and shear. A crease in folded paper is an example of a fold axis.

In a preferred embodiment, the tissue adhesive component of the dressingis formed from a freeze phase separated and dried chitosan sheet withcomposition including a catechol chitosan. In a preferred embodiment thenon-tissue adhesive component of the dressing is formed from a freezephase separated chitosan dried sheet without any modified chitosan. In apreferred embodiment, both tissue adhesive and non-tissue adhesive drysheets have density ≤about 0.03 g/cm³ before compression to finaldensity ≥about 0.4 g/cm³.

In order to prepare one dressing from both sheets with the dressinghaving a tissue adhesive surface layer and a non-adhesive surface layer,the two sheets are bonded together by, for example, placing one sheet ontop of the other and applying sufficient uniform pressure over thedressings to compress them to a higher density. In a preferred process,the original densities of each sheet type at ≤about 0.03 g/cm³ isincreased to a final dressing density ≥about 0.30 g/cm³. In a morepreferred process, the original densities of each sheet type at ≤about0.015 g/cm³ is increased to a final dressing density ≥about 0.4 g/cm³.In a most preferred process, the original densities of each sheet typeat ≤about 0.01 g/cm³ is increased to a final dressing density ≥about 0.5g/cm³. At the conclusion of the compression, the two compressed sheetsare bonded together so that one cannot be readily peeled away from theother and the dressing can be manipulated by folding and furling withoutany occurrence of separation.

This physical adherence of materials by compression of two or more lowdensity porous materials together to form a final two or more layerporous material of higher density solves a difficult problem of how toadhere such materials together without physical or chemical change tothe individual materials and without addition of further bonding agentsor adherents. It is contemplated that bonding may be attributed tomicrosurface impingement and penetration of the dressings through theirpores with physical interlocking due to pore compression. This physicalinterlocking of low density, freeze phase separated, dry sheets is notrestricted to two materials of the same thickness or to only two layerssince the interlocking effect is neither sidedness nor thicknessdependent. Therefore a multi-layered construct of individual freezephase separated and dried sheets of the same or different materials ofthe same or different thickness may be formed by layering the lowdensity sheets (preferably with density ≤0.05 g/cm³) and compressing theassembly together to a density ≥0.3 g/cm3). Such a final physicallyadhered assembly would be expected to provide advantages of thin top andbottom surface layers including but not limited to adhering oranti-adhering materials with layers inside providing including but notlimited to structural, physical and chemical elements.

In some embodiments, a chitosan dressing has an adhesive side and anon-adhesive side. In some embodiments, the adhesive side of thechitosan adheres to a tissue and absorbs and/or redirects the surfacemoisture. In some embodiments, the non-adhesive side detaches from adelivery device upon attachment of the chitosan dressing to the injurysite wherein the chitosan dressing has become wet. This is in partbecause the adhesion strength of the chitosan dressing to the tissuesurface controls the dressing location upon detachment of the dressingfrom the delivery device. Detach or “readily detach” as used herein in atwo-sided chitosan dressing indicates that the chitosan dressing, withits adherent side applied to a tissue surface or an injury site andadhered due to absorbance of moisture, stays at the tissue surface orinjury site while the non-adherent side releases from the deliverydevice, thereby allowing the delivery device to be retracted from theinjury site without disrupting the position of the chitosan dressing onthe tissue surface or injury site. In some embodiments, the chitosandressing, when dry, attaches to the delivery device, thereby allowingdelivery of the chitosan dressing along with the device onto an injurysite.

In one embodiment, there is a need to attach the dressing locally to thedelivery device. Generally, these local attachment areas are at theextremity of the dressing. For example, one design is to provide forlocal pinpoint attachment on the dressing extremity tabs at thecircumference of the dressing and for no other attachment locations toavoid the risk of attaching the dressing to the delivery sheath, thedelivery device, or itself (when furled/folded). The attachmentlocations may be designed to weaken when wet or alternatively beactivated for release by some type of physical release mechanism.

In one mechanism, chitosan dressing provided in this disclosure is ableto stop bleeding by absorbing, channeling, and/or redirecting thehydrophilic and hydrophobic fluids at an injury site. The absorptionclears enough moisture from the injury site to allow subsequenthemostatic reactions between the chitosan dressing and the tissue at theinjury site, which in turn stops bleeding and allows the chitosandressing to stay attached; thus, sealing the injury site. The porous,dense, and multi-layer structure of chitosan dressing provided hereinfacilitates the absorption, channeling, and/or redirection of themoisture at the injury site, and the attachment or adherence of thechitosan dressing to the injury site.

The chitosan dressing disclosed herein is biocompatible. In someembodiments, the dissolved residue from a chitosan dressing applied toan injury site in vivo passes safely through the urethra and is excretedalong with other bodily waste.

More than one, or multiple, chitosan dressings may be used or applied inserial fashion to a tissue treatment site or injury site. When more thanone chitosan dressing is deployed, such dressings may separately adhereto adjacent tissue site or injury site areas, or may overlap with eachother to varying extents. Due to the thinness of the chitosan dressingdescribed herein, depending on the application, it is contemplated thatmultiple chitosan dressings may be used as needed to promote or achievehemostasis of an injury site.

In one embodiment, the chitosan dressings overlap one another uponapplication. In such an instance, ideally there would be some adherenceof the wetted adhesive side of the subsequent dressing to the wetteddressing backing of the earlier dressing. Accordingly, in oneembodiment, the chitosan dressing does not have an anti-adherent backingbut does have a backing with a weak wet adherence that provides forsufficient adherence for placement of a subsequent overlapping chitosandressing.

Delivery Device

A delivery device, as used herein, is a device for delivering adressing, such as a chitosan dressing, to injury sites at differentlocations in the body of an animal including human, pigs, dogs, etc.

In some embodiments, a delivery device can deliver a dressing, e.g., achitosan dressing, to a physiological site in the body of an animal, innon-invasive or minimally invasive manner. In some embodiments, thedelivery device is a balloon device such as, for example, a doubleballoon catheter. In some embodiments, the delivery device is a wiredevice or a device laser-cut from a small diameter cylinder of nitinolor stainless steel. In some embodiments, the non-invasive or minimallyinvasive feature of the delivery device is achieved through delivery ofa dressing, e.g., a chitosan dressing, through a narrow catheter or acomparable working channel. In some embodiments, the balloon catheter orthe comparable working channel has a diameter that is less than about 7mm. In other embodiments, a channel of a TURP delivery device may rangein diameter size from 5 mm to 7 mm.

Exemplary delivery devices include, but are not limited to, a balloondevice, a balloon catheter, a wire device, a cylindrical device withlaser-cut ends, a indwelling catheter, a urethral or suprapubiccatheter, an external catheter, a short-term catheter, and anintermittent catheter.

A delivery device can also be a transluminal or transurethral deliverydevice. In some embodiments, the transurethral delivery device isnon-invasive or minimally invasive due to a narrow catheter ortube/tubing or a similarly narrow-diameter portion of the device.

Delivery devices include other devices with narrow-diameter tubings orcatheters or similar structures.

Attachment of the Dressing to the Delivery Device

TURP dressing attachment to the device, for example, a balloon catheter,is relatively simple. In one embodiment, the circular dressing is foldedonce over itself edge to edge and then the folded dressing (now half) isfolded once again edge to edge of itself (now a quarter). The dressingis unfolded and now there are two fold lines passing through the middleof the dressing. A tracing of the circumference of the catheter is drawnin the middle of the dressing (a small central circle). A scissors pointor other sharp cutting instrument is used to cut along the intersectingfold lines in the middle of the dressing up to the drawn circumferenceof the catheter. Once the fold lines have been cut there are now fourtriangular windows or catheter connection tabs in the middle of thedressing. The catheter can be threaded thru the central opening in thedressing and the dressing tabs can be attached by double sided adhesivetape or other adhesive method of application to secure the tabs againstthe desired location of the catheter to set the bulk of the dressingover and against the catheter balloon. The dressing tabs are preferablyplaced on the side of the dressing facing away from the catheter balloonover which the dressing is to be folded. Preferably the adhesive used toattach the tabs to the catheter is water soluble to allow the dressingto slide off the catheter and be left in place (with optional catheterremoval) after a pressure application by balloon catheter. In somealternative implementations, instead of an adhesive, a releasablemechanical device such as one or more mechanical release ties, can beused to releasably couple the dressing to a balloon catheter.

After the dressing is attached to an injury site and well adhered to thepatient's tissues, the water soluble adhesive or the mechanical devicecoupling the dressing to the balloon catheter can then release thedressing to allow the dressing to stay in place when the catheter isremoved. In some implementations, the catheter may be left in place forsome additional time with the proximal balloon deflated and with thedistal balloon left inflated to cause the catheter to remain in theurethra. Such implementations can allow the catheter to remain in theurethra without uncomfortable traction to assist in urine drainage andto allow a physician to monitor hematocrit in the urine (absence ofhematocrit indicates hemostasis).

Applications and Methods of Treatment

The chitosan dressing provided in this disclosure may be used to stopbleeding in suitable diseases, conditions, disorders, or emergenttraumas or injuries. In some embodiments, the dressing may be used tostop bleeding from any wet physiological surface, e.g., mucus or bladderfluid covered surfaces. Exemplary applications include, but are notlimited to, bladder bleeding, other intraluminal applications, includingvascular applications, internal surgical bleeding, internal biopsybleeding, internal bleeding following parenchymal organ resection, andoral, ocular, auditory or nasal bleeding. Additional applications thatmight require addition of water or fluid to encourage adhesion of thechitosan dressing to a tissue surface or injury site are alsocontemplated, for example, use of the chitosan dressing on external bodysurfaces.

Chitosan dressings of the present invention may be used for treatment oftransurethral prostatectomy and or bladder neck bleeding that mayinclude but not be limited to treatment of bleeding.

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet, includingU.S. Provisional Patent Application No. 62/612,009 filed Dec. 29, 2017,are incorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments.

These and other changes can be made to the embodiments in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the claims to the specificembodiments disclosed in the specification and the claims, but should beconstrued to include all possible embodiments along with the full scopeof equivalents to which such claims are entitled. Accordingly, theclaims are not limited by the disclosure.

CEHD Delivery Device Design

A preferred embodiment of a CEHD delivery device for post-operativetreatment of transurethral prostatectomy (TURP) and a suitable mode todeliver CEHD will be by balloon catheter delivery. Standard of care forbleeding control in TURP is placement of Foley balloon catheter in theurethra and its location over the prostatic injury site with ballooninflation to apply localized pressure at the injury site for 24 hours oras long as bleeding control is required.

The balloon catheter device for CEHD delivery is preferably a doubleballoon device with the first balloon (distal) provided for inflation inthe bladder while the second balloon (proximal) supports the CEHD thatis placed around the balloon. The first balloon, once inflated, is usedto position the uninflated second balloon and CEHD with low tensionalong the catheter so that the first inflated balloon sits against thebladder neck and the second balloon (or delivery balloon) containing theCEHD is aligned with the prostate cavity injury.

The CEHD may be attached to the uninflated delivery balloon by areleasable tape which remains part of the catheter, or it may be furledaround the uninflated balloon. The CEHD is typically applied to thedelivery balloon during final assembly of the device, prior toapplication of a sheath, packaging and terminal sterilization. Prior tointroduction of the catheter to the location of the injury through theurethra, the delivery balloon and CEHD are protected by a close-fitting,water impermeable sheath that can be removed intact immediately prior todelivery balloon inflation. Delivery by (second) balloon inflation afterremoval of the sheath covering provides for application of the tissueadhesive side of the CEHD against the injured prostate tissue surface.It is anticipated that about three minutes to about 120 minutes ofuniform tissue adhesive surface contact of the CEHD to the injuredtissue surface will allow for uniform moderate to strong covalentbinding of the catechol modified chitosan to the injury site. Intimatewet tissue adhesion of the CEHD dressing will result in immediatecontrol of bleeding, protection of the injury site and promotion ofinjury healing. Once the CEHD dressing is adhered to the injury site, adecision may be made to either leave the catheter in place or to removethe catheter leaving the CEHD dressing in place to control bleeding,protect the injury site and promote healing. The CEHD is designed todissolve away in the urethra over about 96 to about 168 hours, allowingthe urethra to remain patent with ability to control the passage ofurine as needed.

The removable sheath is provided to prevent the CEHD from prematurecontact with any liquids during the process of balloon location at thesite of injury prior to sheath removal and ultimate delivery of the CEHDto the injury site. Such premature liquid contact with activation of thedressing could result in adherence to the wrong tissue or causeundesirable fouling of the CEHD surface. The removable sheath locatedover the CEHD is water impermeable. It is preferably formed from atransparent, biocompatible polymer film material that can be sterilizedat ≥about 25 kGy, is uniformly water impermeable, ultimate tensilestrength at about 25±3° C. is preferably ≥about 10 MPa and ≤25 aboutMPa, and % elongation to failure is preferably ≥about 3% and ≤about 25%.Preferably the inside surface of the removable sheath is sufficientlylubricious without use of wetting agents to allow dry, clean slidingpassage of the sheath surface over the CEHD and balloon cathetersurfaces as the sheath is located either on or off the catheterassembly. Preferably the outside surface of the removable sheath issufficiently lubricious dry, or wet with water to allow unhinderedsliding passage of the sheath surface through urethra and area of injurywithout transfer of any bound lubrication and or bound wetting agentfrom the sheath or without need for any other external lubricationagent. The removable sheath may be formed of a cylinder that closelyfits around the CEHD and balloon. The distal end of the cylinder may beclosed and impermeable to water and this end may fit over the distal endof the balloon catheter and over the first balloon. The proximal end ofthe cylinder will contain the proximal end of the balloon catheter whichis not placed into the urethra and this end may be left open.Alternatively, the distal end of the sheath cylinder may be initiallyleft open to be adhered to the balloon catheter surface to create awater impermeable seal on the balloon catheter at the distal end of thesecond balloon.

The distal end of the sheath enclosing and protecting the CEHD may bereleased from attachment to, or enclosing, the balloon catheter bycomplete, localized, circumferential rupture of the distal end of thesheath. Such localized rupture may be accomplished by application of atearing pull thread positioned distally and circumferentially at thedesired location. The other end of the pull thread would be located atthe open proximal end of the sheath. The sheath may be weakeneddistally, and circumferentially by local reduction in the sheath wallthickness such that application, either of a tearing thread, or inducedloading at that location would result in the desired completecircumferential sheath rupture. The induced loading may be accomplishedby moderate balloon inflation (first balloon in the case of the distalclosed sheath cylinder end; second balloon in the case of the distalcylinder end adhered to the catheter distal to the second balloon) or bypulling of the sheath end outside of the urethra in a proximaldirection. To avoid premature detachment of the sheath during passage ofthe catheter through the urethra, the friction load on the sheath duringplacement of the catheter will be significantly below (≤about ⅓) thedesigned distal end circumferential rupture used to remove the sheath.Once the distal end of the sheath is released, then pulling of theproximal end of the sheath out of the urethra would result in removal ofthe sheath from the delivery balloon and provide for unhinderedapplication of the CEHD against the injury site surface by balloonpressure. Removal of the sheath may also be facilitated by locallongitudinal sheath wall thinning from distal end to proximal end of thesheath. Such longitudinal wall thinning or weakening as a singlelongitudinal line or multiple longitudinal lines provides for ability toremove the sheath rapidly and completely from the catheter balloon in asingle, or in multiple long complete strips while the balloon is presentinside the urethra. One option to ensure that the longitudinal strips ofthe ruptured sheath do not tear circumferentially when being withdrawnis to apply longitudinal sheath reinforcement in the ruptured sheaths.Such longitudinal reinforcement might include higher modulus adherentstrips or fiber within or adhered on the sheath.

CEHD Foley Catheter Delivery Balloon Design

A preferred embodiment in the treatment of transurethral prostatectomy(TURP) and a suitable mode of CEHD delivery will be by balloon delivery.Standard of care for bleeding control in TURP is placement of Foleycatheter balloon in the urethra and its location over the prostaticinjury site with balloon inflation to apply localized pressure at theinjury site for 24 hours or as long as bleeding control is required.

The balloon catheter device for CEHD delivery is preferably a doubleballoon device with the first balloon (distal) provided for inflation inthe bladder while the second balloon (proximal) supports the CEHD thatis placed around the balloon. The first balloon, once inflated, is usedto position the uninflated second balloon and CEHD with low tensionalong the catheter so that the first inflated balloon sits against thebladder neck and the second balloon (or delivery balloon) containing theCEHD is aligned with the prostate injury.

The CEHD may be attached to the uninflated delivery balloon by areleasable tape which remains part of the catheter, or it may be furledaround the uninflated balloon. The CEHD is typically applied to thedelivery balloon during final assembly of the device, prior toapplication of sheath, packaging and terminal sterilization. Prior tointroduction of the catheter to the location of the injury through theurethra, the delivery balloon and CEHD are protected by a close-fitting,water impermeable sheath that can be removed intact immediately prior todelivery balloon inflation. Delivery by (second) balloon inflation afterremoval of the sheath covering provides for application of the tissueadhesive side of the CEHD against the injured prostate tissue surface.It is anticipated that about three minutes to about 120 minutes ofuniform tissue adhesive surface contact of the CEHD to the injuredtissue surface will allow for uniform moderate to strong covalentbinding of the catechol modified chitosan to the injury site. Intimatewet tissue adhesion of the CEHD dressing will result in immediatecontrol of bleeding, protection of the injury site and promotion ofinjury healing. Once the CEHD dressing is adhered to the injury site, adecision may be made to either leave the catheter in place or to removethe catheter leaving the CEHD dressing in place to control bleeding,protect the injury site and promote healing. The CEHD is designed todissolve away in the urethra over about 96 to about 168 hours, allowingthe urethra to remain patent with ability to control the passage ofurine as needed.

The removable sheath is provided to prevent the CEHD from prematurecontact with any liquids during the process of balloon location at thesite of injury prior to sheath removal and ultimate delivery of the CEHDto the injury site. Such premature liquid contact with activation of thedressing could result in adherence to the wrong tissue or causeundesirable fouling of the CEHD surface. The removable sheath locatedover the CEHD is water impermeable. It is preferably formed from atransparent, biocompatible polymer film material that can be sterilizedat ≥about 25 kGy, is uniformly water impermeable, ultimate tensilestrength at about 25±3° C. is preferably ≥about 10 MPa and ≤about 25MPa, and % elongation to failure is preferably ≥about 3% and ≤about 25%.Preferably the inside surface of the removable sheath is sufficientlylubricious without use of wetting agents to allow dry, clean slidingpassage of the sheath surface over the CEHD and balloon cathetersurfaces as the sheath is located either on or off the catheterassembly. Preferably the outside surface of the removable sheath issufficiently lubricious dry, or wet with water to allow unhinderedsliding passage of the sheath surface through the urethra and area ofinjury without transfer of any bound lubrication and or bound wettingagent from the sheath or without need for any other external lubricationagent. The removable sheath may be formed of a cylinder that closelyfits around the CEHD and balloon. The distal end of the cylinder may beclosed and impermeable to water and this end may fit over the distal endof the balloon catheter and over the first balloon. The proximal end ofthe cylinder will contain the proximal end of the balloon catheter whichis not placed into the urethra and this end may be left open.Alternatively, the distal end of the sheath cylinder may be initiallyleft open to be adhered to the balloon catheter surface to create awater impermeable seal on the balloon catheter at the distal end of thesecond balloon. The distal end of the sheath enclosing and protectingthe CEHD may be released from attachment to, or enclosing, the ballooncatheter by complete, localized, circumferential rupture of the distalend of the sheath. Such localized rupture may be accomplished byapplication of a tearing pull thread positioned distally andcircumferentially at the desired location. The other end of the pullthread would be located at the open proximal end of the sheath. Thesheath may be weakened distally, and circumferentially by localreduction in the sheath wall thickness such that application, either ofa tearing thread, or induced loading at that location would result inthe desired complete circumferential sheath rupture. The induced loadingmay be accomplished by moderate balloon inflation (first balloon in thecase of the distal closed sheath cylinder end; second balloon in thecase of the distal cylinder end adhered to the catheter distal to thesecond balloon) or by pulling of the sheath end outside of the urethrain a proximal direction. To avoid premature detachment of the sheathduring passage of the catheter through the urethra, the friction load onthe sheath during placement of the catheter will be significantly below(≤⅓) the designed distal end circumferential rupture used to remove thesheath. Once the distal end of the sheath is released then pulling ofthe proximal end of the sheath out of the urethra would result inremoval of the sheath from the delivery balloon and provide forunhindered application of the CEHD against the injury site surface byballoon pressure. Removal of the sheath may also be facilitated by locallongitudinal sheath wall thinning from distal end to proximal end of thesheath. Such longitudinal wall thinning or weakening as a singlelongitudinal line or multiple longitudinal lines provides for ability toremove the sheath rapidly and completely from the catheter balloon in asingle, or in multiple long complete strips while the balloon is presentinside the urethra. One option to ensure that the longitudinal strips ofthe ruptured sheath do not tear circumferentially when being withdrawnis to apply longitudinal sheath reinforcement in the ruptured sheaths.Such longitudinal reinforcement might include higher modulus adherentstrips or fiber within or adhered on the sheath.

FIGS. 2A-2I illustrate a method of preparing a dressing as describedherein and an associated delivery system for delivering the dressing toa desired location within a patient's body. As illustrated in FIG. 2A,the dressing may have an overall circular shape and four fold lines,each of which extends along a diameter of the circle and through thecenter of the circle, and which together evenly divide the circularshape into eight equal-area segments of the overall circular shape. Asillustrated in FIG. 2A, an operator can cut a cross along twoperpendicular fold lines at the center of the dressing to create acruciform-shaped opening at the center of the dressing. As illustratedin FIGS. 2A-2C, the operator can then fold the dressing along all fourof the fold lines to form peaks along two perpendicular fold lines andvalleys along the other two perpendicular fold lines when the dressingis viewed on-end.

As the dressing is folded up in this manner, the dressing eventuallyforms four dual-layered arms that extend radially outward from acenterline of the dressing, with the cruciform-shaped opening at one endof the dressing along the centerline of the dressing. As illustrated inFIG. 2D, the operator can then extend the distal end of a deliverysystem, such as a balloon catheter, first through the cruciform-shapedopening and then through the rest of the body of the dressing along thecenterline of the dressing until the dressing is located radiallyoutward from, and extends circumferentially around a balloon of theballoon catheter. As illustrated in FIGS. 2E-2G, the operator can thenwrap the four arms of the dressing into a spiral configuration about therest of the delivery system to reduce the overall profile of thedelivery system combined with the dressing. As illustrated in FIGS. 2Hand 2I, a protective sheath can then be positioned to surround thedelivery system and the dressing to prepare the delivery system anddressing for delivery to a location inside a patient's body.

In some embodiments, the delivery system may be a single ballooncatheter having a single independently actuatable balloon, and thedressing may be positioned on, or over, or directly radially outwardfrom, the balloon. FIGS. 1A-1D illustrate operation of such a singleballoon catheter to deliver the dressing to a desired location inside apatient's bladder. For example, FIG. 1A illustrates that the ballooncatheter can be inserted into the patient's urethra and extended throughthe urethra until the balloon of the balloon catheter is located withinthe patient's bladder. Once the balloon of the balloon catheter islocated within the patient's bladder, the distal end of the protectivesheath can be ruptured and then withdrawn along the length of theballoon catheter through the patient's urethra. Once the protectivesheath is removed in this manner, the balloon catheter can be actuatedto inflate and expand the balloon, and can be retracted proximally sothat the inflated balloon rests against the neck of the patient'sbladder, as illustrated in FIG. 1A. This may press the dressing againstthe wall of the patient's bladder and hold the dressing in place, suchas adjacent to the neck of the bladder, such as to adhere the dressingto the wall of the patient's bladder, such as to repair an injury and/orprevent bleeding at such a location, as illustrated in FIGS. 1B-1D. Oncethe dressing has been delivered in this manner, the balloon can bedeflated and the balloon catheter can be retracted out of the patient'sbladder through the urethra.

In other embodiments, the delivery system may be a double ballooncatheter having two independently actuatable balloons, a first, distalballoon, and a second, proximal balloon, and the dressing may bepositioned on, or over, or directly radially outward from, the proximalballoon. FIGS. 1E-1G illustrate operation of such a double or dualballoon catheter to deliver the dressing to a desired location inside apatient's bladder. For example, FIG. 1E illustrates that the ballooncatheter can be inserted into the patient's urethra and extended throughthe urethra until the balloons of the balloon catheter are locatedwithin the patient's bladder. Once the balloons of the balloon catheterare located within the patient's bladder, the distal end of theprotective sheath can be ruptured and then withdrawn along the length ofthe balloon catheter through the patient's urethra. Once the protectivesheath is removed in this manner, the balloon catheter can be actuatedto inflate and expand the distal balloon, and can be retractedproximally so that the inflated balloon rests against the neck of thepatient's bladder, as illustrated in FIG. 1F. In some implementations,the sheath is not ruptured and removed prior to inflation of the distalballoon, and inflation of the distal balloon ruptures the sheath andallows the sheath to be removed along the length of the balloon catheterthrough the patient's urethra.

These actions may leave the proximal balloon and the dressing adjacent aresected prostatic fossa. Once the distal balloon is inflated and theprotective sheath is removed in this manner, the balloon catheter can beactuated to inflate and expand the proximal balloon. This may expand andunfold or unfurl and press the dressing against a wall of the patient'sbladder, urethra, and/or resected prostatic fossa, and hold the dressingin place, such as adjacent to the resected prostatic fossa, such as toadhere the dressing to the resected prostatic fossa, such as to repairan injury and/or prevent bleeding at such a location, as illustrated inFIG. 1G. Once the dressing has been delivered in this manner, theballoons can be deflated and the balloon catheter can be retracted outof the patient's bladder through the urethra.

FIGS. 3A-3F illustrate systems and methods for operating a doubleballoon catheter to deliver a dressing to a patient. For example, anupper portion of FIG. 3A illustrates a double balloon catheter and alower portion of FIG. 3A illustrates a larger view of portions of FIG.3A. The left side portion of FIG. 3B illustrates an end view of apartially-folded dressing, and a right side portion of FIG. 3Billustrates a side view of a partially-folded dressing. The upperportion of FIG. 3C illustrates a partially folded dressing positioned ona balloon catheter, and the lower portion of FIG. 3C illustrates acompletely folded dressing positioned on a balloon catheter with asheath surrounding the dressing and the balloon catheter. FIG. 3Dillustrates the dressing, balloon catheter, and sheath of the lowerportion of FIG. 3C positioned within a patient's urethra and bladder.FIG. 3E illustrates another completely folded dressing positioned on aballoon catheter with a sheath surrounding the dressing and the ballooncatheter. FIG. 3F illustrates the dressing, balloon catheter, and sheathof FIG. 3E positioned within a patient's urethra and bladder.

In some implementations, a pair of dressings can be loaded onto aballoon catheter, such as onto a single balloon of a balloon catheter,largely in accordance with the description above for loading a singledressing onto a balloon of a balloon catheter. For example, an operatorcan obtain two dressings in accordance with the description above. Theoperator can cut a cross along two perpendicular fold lines at thecenter of each of the two dressings to create a cruciform-shaped openingat the center of each of the dressings. The operator can then fold eachof the dressings along their respective fold lines as described above.As the dressings are folded up in this manner, each of the dressingsforms four dual-layered arms that extend radially outward from acenterline of the dressing, with the cruciform-shaped opening at one endof the dressing along the centerline of the dressing. A bottom portionof FIG. 4 illustrates two dressings partially folded in this mannerwithout openings cut at the centers of the dressings.

The operator can then extend the distal end of a balloon catheter, firstthrough the cruciform-shaped opening and then through the rest of thebody of a first one of the dressings along the centerline of the firstone of the dressings until the first one of the dressings is locatedradially outward from, and extends circumferentially around a balloon ofthe balloon catheter. The operator can then extend the distal end of theballoon catheter, first through the end thereof opposite to thecruciform-shaped opening and then through the rest of the body and outof the cruciform-shaped opening of a second one of the dressings alongthe centerline of the second one of the dressings until the second oneof the dressings is located radially outward from, and extendscircumferentially around a balloon of the balloon catheter. In suchimplementations, the first and second ones of the dressings may bemounted onto the balloon catheter over the same, or over differentballoons of the balloon catheter. The operator can then wrap the fourarms of each of the dressings into a spiral configuration about the restof the delivery system to reduce the overall profile of the deliverysystem combined with the dressings. A protective sheath can then bepositioned to surround the delivery system and the dressings to preparethe delivery system and dressings for delivery to a location inside apatient's body.

In some embodiments, the delivery system may be a single ballooncatheter having a single independently actuatable balloon, and the firstand second ones of the dressings may be positioned on, or over, ordirectly radially outward from, the balloon. A top portion of FIG. 4illustrates operation of such a single balloon catheter to deliver thetwo dressings to a desired location inside a patient's bladder. Forexample, the top portion of FIG. 4 illustrates that the balloon cathetercan be inserted into the patient's urethra and extended through theurethra until the balloon of the balloon catheter is located within aresected prostatic fossa adjacent the patient's bladder. Once theballoon of the balloon catheter is located within the resected prostaticfossa in this manner, the distal end of the protective sheath can beruptured and then withdrawn along the length of the balloon catheterthrough the patient's urethra. Once the protective sheath is removed inthis manner, the balloon catheter can be actuated to inflate and expandthe balloon. This may press the dressings against the walls of theresected prostatic fossa adjacent to the patient's bladder and hold thedressings in place, such as adjacent to the neck of the bladder, such asto adhere the dressings to the wall of the resected prostatic fossa,such as to repair an injury and/or prevent bleeding at such a location.Once the dressings have been delivered in this manner, the balloon canbe deflated and the balloon catheter can be retracted out of thepatient's body through the urethra.

EXAMPLES

The following materials and preparations were considered in the chitosanendoluminal hemostatic dressing inventive process.

-   -   Chitosan A: Primex ChitoClear 65010, TM 4375, MW=250-300 kDa,        Brookfield    -   Chitosan B: Primex ChitoClear 43000, TM 4167, MW=110-150 kDa,        Brookfield viscosity in 1.0% w/w chitosan solution in 1.0%        acetic acid at 25° C. and spindle LV1=9 cPs, DDA=95% (by        colloidal titration).    -   Glacial acetic acid: Fisher Scientific, Catalogue No. A38-212.    -   Hydrochloric acid: 1.0 M aqueous solution Sigma Aldrich,        Catalogue No. H9892.    -   L-Lactic acid: JT Baker, Catalogue No. 0196-01.    -   Glycolic acid: JT Baker, Catalogue No. M821-05.    -   Sodium hydroxide: 5.0 M NaOH aqueous solution Sigma Aldrich,        Catalogue No. 58263-150 ml.    -   Potassium hydroxide: 0.1 M KOH in methanol (BDH).    -   Ethanol: 2000 Proof Sigma Aldrich, Catalogue No. 459844-1L.    -   Acetic anhydride: ACS reagent grade obtained from Sigman        Aldrich, Catalogue No. 320102-1L.    -   3,4-Dihydroxyhydrocinnamic acid (hydrocaffeic acid): 98% Sigma        Aldrich, Catalogue No. 102601.    -   3,4-Dihydroxycinnamic acid (caffeic acid): 98% Sigma Aldrich        Catalogue No. C0625    -   trans-3,4-Dihydroxycinnamic acid (trans-caffeic acid): Sigma        Aldrich Catalogue No. 51868    -   3,4-Dihydroxyphenylacetic acid (DOPAC, Homoprotocatechuic acid):        98% Sigma Aldrich Catalogue No. 850217.    -   1-ethyl-3-(-3-dimethylamino-propyl)-carbodiimide: (alternatively        N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride        with common acronym EDC) Sigma Aldrich, Cat. #E7750.    -   N-acetyl-L-cysteine Sigma Aldrich, Catalogue No. A7250    -   Sodium Chloride Sigma Aldrich, Catalogue No. 793566-500g.    -   Glycerol: Sigma Aldrich, Catalogue No. G-8773.    -   Polyethylene glycol: Spectrum, Catalogue No. PO108.    -   Polyethylene oxide: Mw 400,000 da, Sigma Aldrich Catalogue No.        372773-500G.    -   Poloxamer 407: Spectrum, Catalogue No. P1166.    -   Sucrose: Sigma Catalogue No. S3929.    -   D-Sorbitol: Sigma Catalogue S1876    -   Hydroxypropyl cellulose (HPC): Aldrich Catalogue No. 191892    -   Hydroxyethyl cellulose (HEC): Aldrich Catalogue No. 308633.    -   Synthetic urine formulation: Add calcium chloride dihydrate        Sigma Catalogue No. C5080 (1.30 g); magnesium chloride        hexahydrate Sigma Catalogue No. M2670 (1.30 g); sodium chloride        Sigma Catalogue No. 793566 (9.20 g); sodium sulphate Aldrich        Catalogue No. 238597 (4.60 g); sodium citrate dihydrate Sigma        catalogue No. S4641 (1.30 g); sodium oxalate Sigma Catalogue No.        71800 (0.04 g); potassium dihydrogen orthophosphate Sigma        Catalogue No. P5655 (5.60 g); potassium chloride Fisher        Catalogue No. BP366 (3.20 g); ammonium chloride Sigma Catalogue        No. 09718 (2.00 g); urea Sigma catalogue No. U1250 (50.00 g);        creatinine Acros Catalogue No. 228940500 (2.20 g) to a 2.0 liter        volumetric flask and add 1.5 liters of deionized water to        dissolve. After dissolution of ingredients in water and        equilibration of solution temperature to room temperature, make        up to 2.0 L mark with deionized water.    -   Porcine bladder with urethra, Animal Biotech Industries Inc.,        (Danboro, PA 18916)    -   Porcine small intestine casing, Butcher & Packer (29/32 mm)        (Madison Heights, MI 48071)    -   Citrated bovine whole blood: Lampire Biological Laboratory        Bovine CPD, Catalogue No. 7720010.    -   Cynaoacrylate A: Permabond 910 Tissue Adhesive, Catalogue No.        72590.    -   Cyanoacrylate B: Loctite 4902 instant adhesive Catalogue No.        1875841 Dialysis Tubing: 3,500 Da MWCO Snakeskin Dialysis Tubing        (Fisher Scientific), Catalogue No. PI88244.    -   Parafilm: “M” Laboratory film, Pechiney plastic packaging        (Chicago, IL 60631)    -   Adhesive: Double sided 3M Catalogue No. 21200-46144-6 (St Paul,        MN 55144)    -   Scotch Fine Line Tape 218, 3M Catalogue No. 70-0060-4397-3 (St        Paul, MN 55144)

Example 1 Preparation of Catechol Chitosan and Characterization

Catechol chitosan synthesis is an N-acylation reaction between acatechol molecule containing a terminal carboxylic acid and the C-2amine of glucosamine mer of the chitosan (See FIG. 7 ). The reaction isperformed at controlled pH in dilute aqueous solution at roomtemperature. Table 1 (FIG. 18 ) provides a number of examples ofcatechol modified formulations used in the preparation of the invention.Column 1 of Table 1 provides a list of dressing preparations. Theformulations of the preparations are listed in column 2 of Table 1.Catechol chitosan formulations have an acronym of “Cs-Cat”. The Cs-Catformulation number is provided immediately after the “Cs-Cat” and iswritten “Cs-Cat, XX” where XX is a numeric representing the catecholchitosan formulation number. Chitosan solutions were prepared and theseare written as “Chitosan” or “Cs” typically with the acid (lactic oracetic) used to provide aqueous solution. HPMC is hydroxypropylmethylcellulose. HPC is hydroxypropyl cellulose whereas HEC is hydroxyethylcellulose. Chitosa lots are shown in column 3. The catechol degree ofsubstitution of the chitosan (column 4 of table 1) was determined asfollows:

-   -   Quartz UV test cells, 1 cm path length, ×2 (HACH Co., cat        #48228-00) were used in acquiring UV/vis spectra. The UV/Vis        spectrophotometer was a Varian Cary Bio 100.

Standard solutions of 3,4-dihydroxyhydrocinnamic acid were prepared inwater and absorbance at 280 nm was plotted against concentration. Theextinction coefficient 8 in the Beer Lambert relationship shown belowfor absorbance in dilute solution

A=ε·c·l

A is absorbance (dimensionless) and l is the path length.

(Absorbance <0.5) was determined as 2,540±50 liter/(mol·cm). This valuewas used to determine degree of substitution in the modified chitosan indilute aqueous solution of known mass of modified chitosan, known volumeof solution and measured peak absorbance at 280 nm.

The chitosan catechol solution is diluted so that its absorbance at 280nm is less than 0.5 (usually about 1:50 or 1:100). The absorbance, theweight of the solution used in the dilution, and the percent solids(CS-catechol) were used to find the fractional degree of substitution(f_(DS)) of the HCA with respect to free amines on the chitosan backboneaccording to the equations:—

$f_{DS} = \frac{n_{HCA}}{f_{DDA}.n_{{total}{Chitosan}{mers}}}$$f_{DS} = \frac{A \cdot {V.\left\{ {\left( {f_{DDa} \cdot 161} \right) + \left( {1 - {f_{DDA} \cdot 203}} \right)} \right\}}}{\varepsilon \cdot l \cdot \left\{ {m_{cc} - \left( {{\frac{A \cdot V}{\varepsilon \cdot l} \cdot 16}{5.1}7} \right)} \right\} \cdot f_{DDA}}$

where A is UV/vis absorbance at 280 nm of the modified chitosan; V isthe volume (liters) of the modified chitosan solution taken to dry toconstant dry mass; m_(CC) is the measured dry mass (g) of the catecholmodified chitosan; f_(DDA) is the fractional degree of deacetylation ofthe chitosan.

The percentage solute (primarily hydrophilic polymer) in the solutionsis shown in column 5 of Table 1. The depth of solution poured into theflat well mold for freeze phase separation is provided in column 6 ofTable 1. On freezing the depth of pour remains substantially unchangedso that after freeze drying the depth of pour provides a helpfulindicator for the extent of compression change when referencing a thefinal set of the compressed dressing (provided in column 7 of Table 1).The final density of the dry compressed dressing is provided in column 8of Table 1. Column 9 of Table 1 provides any additional informationregarding the dressing preparation. It is interesting to note that thedressing 17 preparation was carried to a high degree of dryness whiledressing preparations 71, 79, 80, 83, 84 and 85 were all performed withco-compression of a non-catechol chitosan dressing. These non-catecholchitosan dressings used as backings were all formed from 5 mm poured43000 0.5% w/w chitosan acetic acid solution.

Examples of the catechol chitosan syntheses are given in the 6 approachvariants provided below.

Approach 1 CS-Catechol, Batch 15:

Chitosan (1.51 g) was dissolved in deionized water (140 g) with 1.0 MHCl (5 mL). A 1:1 v/v solution (145 mL) of deionized water to ethanolwas prepared. 3,4-dihydroxyhydrocinnamic acid (HCA; 10.5 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC; 13.0mmol) were dissolved in the water/alcohol solution. Next, thewater/alcohol solution was slowly added to the chitosan solutionprepared above and the reaction mixture was put on stirring. The pH ofthe reaction mixture was maintained at 5.5 using 5.0 M NaOH solution andleft to react overnight. After reacting overnight, the solution wasdialyzed against 5 L of deionized water acidified with 1 drop of 1.0 MHCl solution for three days and against deionized water for 4 hours.Dialysate was changed periodically (at least every 24-48 hours)throughout the duration of the dialysis.

Approach 2 CS-Catechol, Batch 22-1:

Chitosan (9.03 g) was dissolved in deionized water (126 g) with 1.0 MHCl (30 mL). The pH of the solution was then brought to 5.1 using 1.0 MNaOH solution. A 1:1 v/v solution (150 mL) of deionized water to ethanolwas prepared and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (EDC; 31.3 mmol) was dissolved in the water/alcoholsolution. 3,4-dihydroxyhydrocinnamic (HCA; 15.7 mmol) was dissolved inof deionized water (15 mL). Next, the HCA solution was slowly added tothe chitosan solution prepared above and the reaction mixture was putunder overhead stirring. The EDC solution was then added slowly to theHCA/chitosan solution. The pH of the reaction mixture was maintained at4.9 using 0.1 N KOH in methanol solution. After reacting overnight, thesolution was dialyzed against 5 L of deionized water acidified with 1drop of 1.0 M HCl solution for four days. Dialysate was changedperiodically (at least every 24-48 hours) throughout the duration of thedialysis.

Some of the solution isolated from CS-catechol, batch 22 after dialysiswas placed in an oven to concentrate the solution. The solution wasbaked at 80 C and the volume decreased by approximately one third.

Approach 3 CS-Catechol, Batch 32 (Prototype A, Acute In-Vivo I):

Chitosan (1.504 g) was dissolved in deionized water (143.5 g) with 1.0 MHCl solution (5.0 mL). The pH of the solution was then brought up to 5.5with 1.0 M NaOH solution. A 1:1 v/v solution (150 mL) of deionized waterto ethanol) was prepared andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC; 2.93mmol) and 3,4-dihydroxyhydrocinnamic (HCA; 10.41 mmol) were dissolved inthe water/alcohol solution. Next, the water/alcohol reactant solutionwas slowly added to the chitosan chloride solution. The pH wascontrolled between 4.9 and 5.5 during addition of the reactants to thechitosan solution using 1.0 M NaOH solution. After addition of thereactants, the reaction mixture was monitored for 2-4 hours and the pHwas controlled between 5.4 and 5.7 using drops of 1.0 M HCl and 1.0 MNaOH as needed. Next, pH was controlled to 5.5 and left to reactovernight. After reacting overnight (approximately 18-24 hours), the pHof the chitosan catechol solution was controlled back to 5.5. Next, thechitosan catechol solution was dialyzed against 5 L of deionized waterat approximately pH 5.8 for 5 days, and against deionized water atapproximately pH 6.1 for 4-24 hours. Dialysate was changed periodically(at least every 24-48 hours) throughout dialysis procedure.

Approach 4 CS-Catechol, Batch 33

Chitosan (0.507 g) was dissolved in deionized water (47.5 g) with 1.0 MHCl solution (2.0 mL). The pH of the solution was brought up to 5.5using 5.0 M NaOH solution. A 1:1 v/v solution (50 mL) of deionized waterto ethanol was prepared andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC; 2.94mmol) and 3,4-dihydroxyhydrocinnamic (HCA; 1.49 mmol) were dissolved inthe water/alcohol solution (-reactant solution-). Next, the reactantsolution was slowly added to the chitosan chloride solution. The pH wascontrolled between 5.4 and 5.6 for 2.5 hours. Then, the pH wascontrolled down to 5.4 and left to react overnight (approximately 18-24hours). The resulting chitosan catechol solution was pH controlled toapproximately 5.5 and subsequently dialyzed at approximately pH 5.8 for3 days and deionized water for 3 days. The dialysate was changedperiodically throughout the dialysis procedure. After dialysis, thesolution was allowed to evaporate excess water gained during dialysis byhanging the solution in the dialysis tubing in a fume hood overnight.The solution was left until it returned to its pre-dialysis weight.

Approach 5 CS-Catechol, Batch 35

Chitosan (1.681 g+10.6% w/w moisture) was dissolved in deionized water(143.5 g) with 1.0 M HCl solution (11 mL). The pH of the chitosanchloride solution was then brought up to approximately 5.5 with 1.0 MNaOH solution. A 1:1 v/v solution (150 mL) of deionized water andethanol was prepared and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (EDC; 8.76 mmol), 3,4-dihydroxyhydrocinnamic (HCA; 2.39mmol), and N-acetyl-L-cysteine (NAC; 2.36 mmol) were dissolved in thewater/alcohol solution (-reactant solution-). Next, the reactantsolution was added to the chitosan chloride solution. The pH of thereaction mixture was controlled between 5.2 and 5.3 during the additionof the reactant solution. After 2 hours, the pH of the reaction mixturewas brought up to approximately 5.4. The solution was then left to reactovernight (approximately 18-24 hours). After reacting overnight, the pHof the solution was controlled up to approximately 5.5. The solution wasdialyzed against 5 L of deionized water for 6 days. The dialysate waschanged periodically (at least every 24-48 hours) throughout thedialysis procedure.

Approach 6 CS-Catechol, Batch 38

Chitosan (1.678 g+10.6% w/w moisture) was dissolved in deionized water(143.3 g) with 1.0 M HCl solution (8 g). The pH of the chitosan chloridesolution was then brought up to approximately 5.5 with 1.0 M NaOHsolution. A 1:1 v/v solution (150 mL) of deionized water and ethanol wasprepared and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (EDC; 2.95 mmol), 3,4-dihydroxyhydrocinnamic (HCA; 1.475mmol were dissolved in the water/alcohol solution (-reactant solution-).Next, the reactant solution was added to the chitosan chloride solution.The pH of the reaction mixture was controlled at close to pH 5.5 duringthe addition of the reactant solution. After 2 hours, the pH of thereaction mixture was adjusted up to 5.51. The solution was then left toreact in a covered beaker a room temperature for 20 hours. After 20hours, the pH of the solution was 5.54. The solution was divided into 3lots of close to 100 g solutions in dialysis tubing and dialyzed against5 L of deionized water for 5 days with pH at 5.8-5.9 on the first 3 daysand pH 6.2 on the fourth day. The dialysate was changed regularly (every24 hours) throughout the dialysis procedure.

Example 2 Freeze Phase Separated Hydrophilic Polymer Dressings

Hydrophilic polymer aqueous solutions were prepared inside 500 ml, 1000ml or 2000 ml Nalgene LDPE bottles or polypropylene beakers by additionof components including but not limited to pre-prepared solution,hydrophilic polymer, water, acid, and additional components. Table 1lists 85 of the formulation types that were investigated.

The main problems experienced when formulating for the transuretheralprostatectomy application with dressings in direct contact with urinewere: 1) rapid (generally <30 mins) urine promoted dissolution ofchitosan; 2) interference from blood in achieving rapid adherence withthe pure catechol modified chitosans; 3) susceptibility to dressingcracking and tearing when making changes to formulations to addressproblems with dissolution and adherence. The final hydrophilic polymersolution % w/w was between 0.1% to 4% by weight polymer. Capped bottlesand their contents were mixed continuously at room temperature over12-24 hours to achieve full solution homogeneity using IKA KS260 orbitalshaker or a Wheaton bench top bottle roller. Beaker solutions were mixedon a magnetic stirrer plate with magnetic stirrer bead at roomtemperature for 12 to 24 hours to achieve solution homogeneity. Parafilmwas used to close the beaker from the external environment duringmixing. The solutions prepared for freeze phase separation weresubstantially homogeneous and clear when suspension conditions were notpresent. The catechol chitosan solutions demonstrated some haze andmilky appearance indicating presence of some dispersed fine catecholchitosan globular particles.

Chitosan solutions were prepared as freeze phase separated dressingswith final solution % weight of hydrophilic polymer in the range 0.25%to 4% w/w aqueous solution. Freeze phase separation was performed inTeflon coated aluminum mold wells with horizontal flat bases. Thesolutions were poured into the wells to a height from the mold base ofpreferably not more than about 10 mm, more preferably 2.5 mm and mostpreferably 5.0 mm. The solutions initially at a temperature in the moldsbefore freezing between 15° C. and 30° C. were then frozen byapplication of cooling through the base of the molds. Although othercooling temperatures may be applied to achieve suitable freeze phaseseparated structure, preferably the applied cooling temperature of theshelf was −40° C., more preferably the cooling temperature was −55° C.and most preferably the cooling temperature was −45° C. After thesolution achieved freezing phase separation and the temperature of thefrozen solution equilibrated at the freezing temperature, the system wasallowed to further freeze phase separate and equilibrate for at least anadditional hour before drying. In a modified freezing and mold fillingmethod to accommodate layers of different freeze phase separatedsolutions, a first layer was added to the mold to a preferred depth andfrozen, a second layer was then added and frozen, a multi-layered freezephase separated dressing could be prepared in this manner. Care wasneeded to ensure there was no frost between an (n−1)th frozen and nthpoured solution and differences in layer frozen structure could resultin cracking. Layering of separate frozen layers adhering together andnot cracking is a significant problem. The discovery of the successfulmethod of layering and adhering of single layer previously driedhydrophilic polymer matrices to a single co-adhered compressedmultilayered composite sheet during this investigation was an unexpectedand significant finding.

A 24 square foot shelf Virtis Benchmark 2000 pilot scale freeze dryerwas used for sublimation freeze drying of the freeze phase separatedfrozen solution plaques. In the primary freeze drying (removal of icenot hydrogen bonded to the hydrophilic polymers), the equilibratedfrozen plaques in their molds were subjected to reduction in pressure≤300 mTorr within the freeze dryer, the freeze dryer condenser was setto ≤−65° C. and the freeze dryer shelves were heated to promotesublimation of the ice from the freeze separated plaques withoutincreasing plaque temperature above −15° C. After removal ofsubstantially all the non-bonded ice, the shelf temperature was raisedto near 25° C. for removal of the hydrogen bonded ice and reduction ofmoisture content in the dried dressing matrix to not more than 4%residual water in the dried dressing matrix. Final dried matricesconformed to the original shape of the filled mold with close to 5%shrinkage in length and width and density between 0.005 g/cm3 and 0.04g/cm3. They contained void space of more than 95% and they wereinterconnected porous structure with fine polymer lamella (submicron to5 micron thickness) and pore spacing between adjacent lamella of 100microns to 300 microns.

After freeze phase separation and drying, the dried matrices werecompressed from their original thicknesses (10 mm to 2.5 mm) to a finalthickness preferably near 50 microns. If two uncompressed dressings werecompressed one on top of the other then they would be permanently bondedtogether at the conclusion of the compression process. Calibrateduniform thickness thin shims may be used in the compression to achieve adesired thickness of compressed dressing substantially the samethickness as the shim. There are a number of ways to achieve thiscompression with a desired compression set near 50 microns. Thepreferred compression method used in the investigation was compressionof the whole dried uncompressed dressing (dimensions typically close to100 mm long×100 mm wide×2.5 mm high or 50 mm diameter×2.5 mm high) withuniaxial compression rate at ≤0.5 mm/min to ≤100 microns thicknessbetween aligned platens. The platens (Diamond sprayed or Teflon coatedMic 6 Aluminum 300 mm×300 mm×90 mm) were machined to flat planar faces(≤5 microns in 300 mm) with none or some controlled texture machinedinto their surface. The temperature of platens during compression wasmaintained preferably near 80° C. over 3-5 minutes of uniaxialcompression. Compression was achieved by screw loading at the fourcorners of the platens at up to four tonnes loading at each corner.Compression was held for at least 2 minutes before release of load. Thenovel compressed hydrophilic polymer matrices were measured forcompression thickness and weight. Final densities were between 0.25 and0.9 g/cm³. After compression, the dressings were further processed. Thisadditional processing included die cutting into 2.5 cm diameter testpieces and in some cases thermal annealing heat treatment (heated in aconvection oven at 60° C.-150° C. for 5-30 minutes). At the conclusionof processing the dressings were placed in foil pouches with zip lock orthermal sealing. Packaged dressings intended for animal andbiocompatibility testing were gamma-irradiated at 25 kGy.

Example 3 In Vitro and Ex-Vivo Testing of Chitosan EndoluminalHemostatic Dressing Prototypes In Vitro Beaker Test

The dissolution behavior of the CEHD was investigated under conditionssimilar to those that would be experienced during TURP in vivo use.Dissolution was monitored for periods up to 7 days to establish that theCEHD dissolution met targeted resistance to early dissolution (in thefirst 24 hours) with subsequent later dissolution so that no residualCEHD would be present after 168 hours (7 days).

Sectioned pieces (25 mm×25 mm×3 mm) of porcine bladder tissue withmucosal surface facing outwards were fixed with cyanoacrylate cement tothe bottom of a 200-milliliter polystyrene beaker. One drop of solutionof 1:250 v/v blood in standard saline was onto the top surface of theex-vivo sectioned bladder tissue. A CEHD dressing piece (1.3 cm×1.9 cm)was applied with 9.7 kPa (73 mmHg) pressure to the wetted tissue surfaceby application of a 500-gram standard weight (Troemner, Thorofare NJ08086) onto a 2.54 cm diameter probe for 5 minutes. Sufficient syntheticurine (50 ml) at room temperature was added to the beaker to submersethe CEHD pieces. The beaker was covered with Parafilm, incubated (FisherScientific Model 146E, CAT. 97-990E) at 37° C., and placed on a shaker(IKA AS260.1, KS 260) at 120 rpm. The synthetic urine solution waschanged every 24 hours and dissolution behavior was documented by amountof dressing visually present at regular intervals until completedissolution, or up until 168 hours. In some tests, CEHD test pieceadhesion to tissue was evaluated by a horizontal scraping movement oftweezers to measure resistance to sheer force. The CEHD tissue adhesiontesting was performed during the in-vitro dissolution testing on a passor fail basis, and noted as low, moderate, or high.

The results of in vitro dissolution and adhesion to porcine bladdermucosa are shown in Table 2 (FIG. 19 ). The in vitro dissolution andadhesion to porcine bladder mucosa results were used together withresults of folding and device deployment testing to select threepreferred dressing types for biocompatibility and in vivo testing. Thesedressing types included catechol modified chitosan preparations andpreparations of both catechol and thiol chitosan modification. Thepreferred pre-in-vivo dressing types were labelled types A, B and C.Dressing Lots 71 and 81 representing type A dressings; Lots 78 and 83representing B type dressings and Lots 75, 80 and 84 representing type Cdressings.

In-Vitro Simulated Venous Wound Sealing (SVWS) Testing

A laboratory simulated venous wound sealing (SVWS) device was built totest the sealing ability of the CEHD adhered by one drop of diluteblood, 1:250 v/v blood in standard saline, with 9.7 kPa load for 5minutes over a 1.5 mm diameter “injury” aperture in the center of astandard PVC plate whose surface had previously been shown to mimicdermis with respect to mucoadhesive chitosan binding to dermis. SilasticLaboratory Tubing, Size—0.250 in I.D.×0.375 in O.D., Dow CorningCorporation (Midland, MI 48686) connected an open reservoir of citratedbovine whole blood to the aperture with a stopper valve immediatelybefore the aperture. The vertical height of the blood level in thereservoir relative above the aperture was adjustable from 0.0 to 50 cm.After a CEHD test dressing was attached centrally over the aperture inthe standard PVC surface the stopper valve was opened and dressings wereobserved for 15 minutes and assessed (pass/fail) on their ability tomaintain sealing (absence of blood leakage through or under the attacheddressing). The pressure head was noted in each test. This test providedrapid simulated bleeding control testing of prototype CEHD's undervenous bleeding pressure.

Simulated bleeding rate (g/min) was determined by weight differencebetween a pre-weighed absorbent sheet and the same absorbent sheetplaced over the “injury” collecting flowing blood for 15 seconds andmultiplying by 4.

A 20 cm to 42 cm head height difference at 23° C. is equivalent to 14.7mmHg to 30.9 mmHg pressure (typical of venous pressure in prostaticbleeding). Bleed rates for the 20 cm and 42 cm height differences weredetermined as 4.7 and 8.0 g/min respectively.

Results of in-vitro simulated venous wound sealing (SVWS) testing areprovided in Table 3 of 25 kGy gamma irradiated dressings Lots B and C(with shelf life in foil packaging at 25° C. temperature storage for 0and 6 months).

TABLE 3 IN-VITRO SIMULATED VENOUS WOUND SEALING (SVWS) TEST RESULTS.Shelf-life Dressing Height (months) type (cm) Test 1 Test 2 Test 3 Test4 Test 5 0 C 21 Pass Pass Pass Pass Pass 0 B 21 Pass Pass Pass Pass Pass6 C 21 Pass Pass Pass 6 B 21 Pass Pass Pass 6 C 42 Pass Pass Pass PassPass 6 B 42 Fail Fail Fail Fail FailEx-Vivo Flow Testing of 10 mm×10 mm Dressing Adhered Over 3 mm DiameterPerforation in SIS

Test dressings that performed well in vitro (dressing types B and C,N=10 each)—see Tables 1 and 2) were adhered under balloon pressure near7 psi for about 3 minutes to porcine small intestine submucosa (SIS)centrally over a 3 mm diameter hole in the SIS supported in an Adams &Chittenden custom manufactured glass test cell (see FIG. 12 ). The testcell containing the dressing adhered to the SIS sealing the defect wasconnected to the flow system depicted in FIG. 13 . A Fisher ScientificFH100M multichannel peristaltic pump with 13-310-911 flow cassettes wasused to provide a controlled rate of flow near 20 ml/min. Syntheticurine near 34° C. to 37° C. and fully filling the volume of the cell wasflowed through the cell at close to 20 ml per minute for 6 to 20 hours.The purpose of the testing was to demonstrate ability of the dressingsto remain adhered to mucosa under flowing urine without tearing or lossof particles or larger pieces from the dressing.

In the case of dressing Type C (dressing Lots 75 and 80), one test wasperformed for 20 hours. At the conclusion of the testing, an externalpressure of 1:250 v/v blood in standard saline near 20 mmHg was appliedthrough the jacketed circuit of the glass test cell to test theadherence of the test dressing to the tissue. The application ofpressure was applied 4 times and the dressing successfully remainedadhered over the 3 mm diameter hole to the internal SIS surfaceresisting the external application of fluid pressure on all 4 pressureapplications. This 20 hour tested dressing was also examined for loss ofmass (by gravimetric comparison of dry weight before and after testing).The gravimetric testing of type C dressing after 20 hours showed thatmaterial loss of catechol modified chitosan (most likely by dissolution)was ≤15% by dry weight of the original dressing. All other tests for thetype C dressings were performed for 6 hours without application of theexternal pressure stress. In the case of the type C dressings, there wasno significant visible dissolution of dressing or any loss of materialfrom the dressings. All dressings remained adhered to the SIS at the endof testing. The adhesion (to SIS mucosa) and cohesion of the dressingswere rated as moderate.

In the case of dressing Lot Type B (dressing Lots 78 and 83) one testwas performed for 24 hours. This 24 hour tested dressing was examinedfor loss of mass (by gravimetric comparison of dry weight before andafter testing). The gravimetric testing of type B dressing after 24hours showed that material loss of catechol modified chitosan (mostlikely by dissolution) was significant at 39.4% by dry weight of theoriginal dressing. All other tests for the type B dressings wereperformed for 6 hours. In the case of the type B dressings, there werevisible indications of significant dissolution of dressing (gelling) andloss of material (visible pieces being released from dressing) from thedressings. The adhesion (to SIS mucosa) and cohesion of the dressingswere rated as moderate to low.

Example 4 Foldability and Deployment Testing of Dressing

All dressing Lots (N≥3) were tested for foldability because this is animportant characteristic for ability to attach, furl and deploy thedressing of the invention against prostatic and bladder neck injurysites. Fold testing involved folding the horizontally planar finalcompressed circular dressing through 180° edge over edge, first in ananticlockwise direction, holding the edges together and compressingfirmly in the middle of the dressing to create a single linear fold axis(or crease) in the dressing. The folded dressing is then opened and theedge to edge fold is reproduced in the new fold axis but with thefolding in the opposite clockwise direction. Foldability success israted as no tears or cracks being visible along the fold axis and nosignificant loss in tensile properties of the dressing (determined bygentle pulling across the fold of the dressing). Results of thefoldability testing are provided in column 4 of Table 2.

Deployment testing (N=5) was performed with preferred chitosan backeddressing types A, B and C using a 250-milliliter volumetric flask filledwith normal saline as a model of a urine filled bladder neck. A fullyassembled device with CEHD dressing, sheath covering and ballooncatheter (distal and proximal balloons) was submerged in the normalsaline below the neck of the volumetric flask. The CEHD application wasinitiated by inflating the distal balloon to break the protectivewaterproof sheath at its distal end, followed by manual complete andintact removal of the torn sheath by pulling on its dry free end outsidethe flask, swift positioning of the distal balloon at the bladder neckfollowed quickly by smooth and rapid inflation of the proximal balloonto open and adhere the dressing against the flask neck. All dressingtypes (A, B and C) were delivered successfully with good adhesion to theglass vessel neck.

Example 5 Biocompatibility of Dressing Types

ISO 10993-1 biocompatibility testing of finished, packaged, sterile(terminal gamma irradiation at 25 kGy) devices was conducted accordingto testing requirements for external communicating devices with indirectblood path contact for limited contact. The tested includedcytotoxicity, dermal irritation and acute systemic toxicity (intriplicate for each test).

Dressing types A and C passed all the biocompatibility testing whiledressing type B failed the acute systemic toxicity testing. It issuspected that gamma irradiation produced a toxic thiol residue in thetype B dressing.

Example 6 Acute In Vivo Bladder Neck and Swine Splenic CapsularStripping Models of Hemostasis

Acute in vivo testing was performed in six domestic female Yorkshireswine, body weight 40-50 Kg (Oak Hill Genetics, CA) and the deliverydevice was assembled with the three CEHD prototypes (Dressing A: n=6;Dressing B: n=9; Dressing C: n=10). The experiment was designed as ablinded randomized study of efficacy of individual prototypes vscontrols in acute swine bladder neck and splenic parenchyma bleedinginjury models.

TABLE 4 STUDY RESULTS ACUTE IN VIVO Dressing Dressing DressingConditions A B C* Control Adherence score in vivo 1.75 ± 1.58 ± 1.7 ±(0-4)‡ 0.29 0.91 0.97 Initial bleeding rate at 5 0.035 ± 0.032 ± 0.039 ±min (ml/min) in bladder .007 .027 .031 neck injury Bleeding rate afterapplied 0.0045 ± 0.0042 ± 0.0034 ± CEHD at 2 hrs in bladder .0029 .0034.0011 neck injury (ml/min) Hemostasis at 30 sec in 1/12 3/12 5/12 0/12†splenic injury mode (ratio) Hemostasis at 3 min in 6/12 7/12 4/12 6/12†splenic injury mode (ratio) *Dressing C was selected to advance to aseven day survival study. ‡0, 1, 2, 3 and 4 = no (material does notadhere), low (adheres but is easily dislodged), moderate (can be removedby probing at edge), moderate to strong (resists removal by probingedge), and strong (probe cannot dislodge edge) adherence respectively.†Surgical gauze was used as negative control for splenic injury model.

Example 7 Seven-Day Survival Study of Control Urethral HemorrhagingUsing Final CEHD Device

The final CEHD prototype delivered by double balloon catheter device wastested in vivo over 7 days against a conventional single balloon Foleycatheter with no CEHD in a prospective randomized study in two tenanimal groups with bleed rate determined by hematuria in the urine priorto injury, 30 minutes after injury, at 1 day at 2 days. After thebladder neck injury was made, the control or test materials were placedat the injury site. In the case of the test article CEHD, initialballoon pressure and traction were maintained for 3 minutes after whichthe traction and balloon pressure were removed. In the case of thecontrol Foley catheter the balloon pressure and traction were appliedagainst the wound as same as for CEHD deployment.

Of twenty swine, four (2 in each arm) were euthanized early and excludedfrom study due to surgery related adverse events including which 3 hadbladder neck/urethral perforation during creating the injury model and 1had tracheal perforation during anesthesia intubation. None of thecontrol or test swine demonstrated material related adverse responses.The following results were obtained from the study: 1) Bleed ratesdecreased significantly in both cases of balloon compression with orwithout CEHD. There was no statistically significant difference betweenthe CEHD group and control group (FIG. 9 ) with respect to bleed rates.2) Histology study showed the bladder neck wounds healed well at 7 daysin both study groups (FIG. 12 ). No CEHD residuals were found at day 7.3) Animals in both groups demonstrated good health over 7 days ofmonitoring, with no signs of adverse events that related to CEHD device.

1-46. (canceled)
 47. An endoluminal hemostatic dressing delivery device,comprising: an endoluminal hemostatic dressing, a distal balloon, and aproximal balloon that is proximal along a length of the delivery devicewith respect to the distal balloon, wherein the endoluminal hemostaticdressing is attached to the proximal balloon, wherein the distalballoon, when inflated, can be used to position the proximal balloon andthe endoluminal hemostatic dressing with low tension along the deliverydevice, wherein the endoluminal hemostatic dressing comprises a modifiedchitosan, and wherein a water impermeable sheath extends around theendoluminal hemostatic dressing.
 48. The endoluminal hemostatic dressingdelivery device of claim 47, further comprising a catheter.
 49. Theendoluminal hemostatic dressing delivery device of claim 47, wherein theendoluminal hemostatic dressing is furled around the proximal balloonand extends radially outwards, wherein the distal balloon, wheninflated, can sit against a neck of a human bladder.
 50. The endoluminalhemostatic dressing delivery device of claim 49, wherein the distalballoon, when inflated, can be used to align the proximal balloon withan injury site, and wherein the proximal balloon when inflated can beused to deliver the endoluminal hemostatic dressing to the injury site.51. The endoluminal hemostatic dressing delivery device of claim 50,wherein the injury site is at a prostate cavity injury, and wherein apart of the endoluminal hemostatic dressing covers the bladder neck. 52.The endoluminal hemostatic dressing delivery device of claim 47, whereinthe endoluminal hemostatic dressing is attached to the proximal balloonby a releasable tape.
 53. The endoluminal hemostatic dressing deliverydevice of claim 47, wherein the endoluminal hemostatic dressing isfurled around the proximal balloon.
 54. The endoluminal hemostaticdressing delivery device of claim 47, wherein the water impermeablesheath can be ruptured before or upon delivery of the endoluminalhemostatic dressing to an injury site.
 55. The endoluminal hemostaticdressing delivery device of claim 47, wherein the endoluminal hemostaticdressing can be in one of a compact condition or in an open condition,wherein the endoluminal hemostatic dressing has a first surface areawhen in the compact condition and a second surface area when in the opencondition, and wherein the second surface area is at least about threetimes larger than the first surface area.
 56. The endoluminal hemostaticdressing delivery device of claim 47 wherein the endoluminal hemostaticdressing comprises catechol modified chitosan.
 57. An endoluminalhemostatic dressing delivery device, comprising: an endoluminalhemostatic dressing, a balloon that can be used to deliver theendoluminal hemostatic dressing to an injury site, and a catheter,wherein the endoluminal hemostatic dressing is attached to the balloon,and wherein the endoluminal dressing comprises a modified chitosan. 58.The endoluminal hemostatic dressing delivery device of claim 57 whereinthe injury site is inside a bladder of a patient.
 59. The endoluminalhemostatic dressing delivery device of claim 57, wherein the balloon canbe aligned with the injury site.
 60. The endoluminal hemostatic dressingdelivery device of claim 59, wherein the injury site is at a prostatecavity injury.
 61. The endoluminal hemostatic dressing delivery deviceof claim 57, wherein the endoluminal hemostatic dressing is attached tothe balloon by a releasable tape.
 62. The endoluminal hemostaticdressing delivery device of claim 59, wherein the endoluminal hemostaticdressing is furled around the balloon, and wherein the balloon can beinflated to deliver the endoluminal hemostatic dressing to the injurysite.
 63. The endoluminal hemostatic dressing delivery device of claim57, further comprising a water impermeable sheath around the endoluminalhemostatic dressing, wherein the water impermeable sheath can beruptured before or upon delivery of the endoluminal hemostatic dressingto the injury site.
 64. The endoluminal hemostatic dressing deliverydevice of claim 57, wherein the endoluminal hemostatic dressing can bein one of a compact condition or in an open condition, wherein theendoluminal hemostatic dressing has a first surface area when in thecompact condition and a second surface area when in the open condition,and wherein the second surface area is at least about three times largerthan the first surface area.
 65. The endoluminal hemostatic dressingdelivery device of claim 57 wherein the endoluminal hemostatic dressingcomprises catechol modified chitosan.
 66. A hemostatic dressing deliverydevice, comprising: a dressing in a compact condition and a balloon,wherein the endoluminal hemostatic dressing is attached to the balloon,wherein the endoluminal dressing comprises catechol modified chitosan,and wherein the balloon, when inflated, can be used to position thedressing in an open condition, wherein the endoluminal hemostaticdressing has a first surface area when in the compact condition and asecond surface area when in the open condition, and wherein the secondsurface area is at least about three times larger than the first surfacearea.
 67. A method, comprising: mounting a dressing onto a balloon of aballoon catheter, the dressing mounted onto the balloon in a compactcondition; inserting the dressing in the compact condition and theballoon of the balloon catheter through a urethra of a patient into abladder of the patient; inflating the balloon to expand the dressingfrom the compact condition to an open condition and to press thedressing against internal tissues of the patient; deflating the balloon;and removing the balloon of the balloon catheter from the bladderthrough the urethra while leaving the dressing in place against theinternal tissues, wherein inflating the balloon to press the dressingagainst internal tissues of the patient includes pressing the dressingagainst the internal tissues for between 3 and 120 minutes, and whereininflating the balloon to press the dressing against the internal tissuesand leaving the dressing in place against the internal tissues stopsbleeding at the internal tissues.
 68. The method of claim 67, whereinthe dressing is capable of stopping bleeding at a blood flow rate ofanywhere within the range of one of (i) 1 ml/min to 5 ml/min, (ii) 1ml/min to 10 ml/min, (iii) 1 ml/min to 15 ml/min, (iv) 1 ml/min to 20ml/min, (v) 1 ml/min to 25 ml/min, (vi) 1 ml/min to 150 ml/min, or (vii)1 ml/min to 200 ml/min at the internal tissues.
 69. The method of claim67, wherein the dressing resists dissolution in bladder fluids at about37° C. for one of (i) at least 6 hours, (ii) at least 12 hours, or (iii)at least 24 hours, or wherein the dressing fully dissolves in bladderfluids at about 37° C. within one of (i) less than about 7 days, (ii)between about 3 days and about 7 days, or (iii) between about 4 days andabout 7 days.
 70. The method of claim 67, wherein the endoluminaldressing comprises catechol modified chitosan.